(Oxo-pyrazolo[1,5a]pyrimidin-2-yl) alkyl-carboxamides

ABSTRACT

Disclosed are compounds of the formula  
                 
 
     and the pharmaceutically acceptable salts thereof where the variables R 1 , R 2 , A, R 4 , R 5 , R 6 , R 6 ′, n, and W are defined herein. These compounds bind to the benzodiazepine site of GABA A  receptors are provided and, therefore can be used to modulate ligand binding to GABA A  receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals.

BACKGROUND OF THE INVENTION

[0001] This application claims priority from U.S. ProvisionalApplication Ser. No. 60/279,147, filed Mar. 27, 2001, the disclosure ofwhich is hereby incorporated by reference in its entirety.

[0002] 1. Field of the Invention

[0003] This invention relates to(oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides that bind and morespecifically to such components to the benzodiazepine site of GABA_(A)receptors. This invention also relates to pharmaceutical compositionscomprising such compounds and to the use of such compounds in thetreatment of central nervous system (CNS) diseases.

[0004] 2. Description of the Related Art

[0005] The GABA_(A) receptor superfamily represents one of the classesof receptors through which the major inhibitory neurotransmitter,γ-aminobutyric acid, or GABA, acts. Widely, although unequally,distributed throughout the mammalian brain, GABA mediates many of itsactions through a complex of proteins called the GABA_(A) receptor,which causes alteration in chloride conductance and membranepolarization. In addition to being the site of neurotransmitter action,a number of drugs including the anxiolytic and sedating benzodiazepinesbind to this receptor. The GABA_(A) receptor comprises a chloridechannel that generally, but not invariably, opens in response to GABA,allowing chloride to enter the cell. This, in turn, effects a slowing ofneuronal activity through hyperpolarization of the cell membranepotential.

[0006] GABA_(A) receptors are composed of five protein subunits. Anumber of cDNAs for these GABA_(A) receptor subunits have been clonedand their primary structures determined. While these subunits share abasic motif of 4 membrane-spanning helices, there is sufficient sequencediversity to classify them into several groups. To date at least 6α, 3β,3γ, 1ε, 1δ and 2ρ subunits have been identified. Native GABA_(A)receptors are typically composed of 2α, 2β, and 1γ subunits (Pritchett &Seeburg Science 1989; 245:1389-1392, and Knight et. al., Recept.Channels 1998; 6:1-18). Various lines of evidence (such as messagedistribution, genome localization and biochemical study results) suggestthat the major naturally occurring receptor combinations are α₁β₂γ₂,α₂β₃γ₂, α_(3β) ₃γ₂, and α₅β₃γ₂ (Mohler et al. Neuroch. Res. 1995; 20(5):631-36).

[0007] The GABA_(A) receptor binding sites for GABA (2 per receptorcomplex) are formed by amino acids from the α and β subunits. Aminoacids from the α and γ subunits together form one benzodiazepine siteper receptor. Benzodiazepines exert their pharmacological actions byinteracting with the benzodiazepine binding sites associated with theGABA_(A) receptor. In addition to the benzodiazepine site (sometimesreferred to as the benzodiazepine or BDZ receptor), the GABA_(A)receptor contains sites of interaction for several other classes ofdrugs. These include a steroid binding site, a picrotoxin site, and abarbiturate site. The benzodiazepine site of the GABA_(A) receptor is adistinct site on the receptor complex that does not overlap with thesite of interaction for other classes of drugs that bind to the receptoror for GABA (see, e.g., Cooper, et al., The Biochemical Basis ofNeuropharmacology, 6^(th) ed., 1991, pp. 145-148, Oxford UniversityPress, New York).

[0008] In a classic allosteric mechanism, the binding of a drug to thebenzodiazepine site increases the affinity of the GABA receptor forGABA. Benzodiazepines and related drugs that enhance the ability of GABAto open GABA_(A) receptor channels are known as agonists or partialagonists depending on the level of GABA enhancement. Other classes ofdrugs, such as β-carboline derivatives, that occupy the same site andnegatively modulate the action of GABA are called inverse agonists. Athird class of compounds exists which occupy the same site as both theagonists and inverse agonists and yet have little or no effect on GABAactivity. These compounds will, however, block the action of agonists orinverse agonists and are thus referred to as GABA_(A) receptorantagonists.

[0009] The important allosteric modulatory effects of drugs acting atthe benzodiazepine site were recognized early, and the distribution ofactivities at different subtype receptors has been an area of intensepharmacological discovery. Agonists that act at the benzodiazepine siteare known to exhibit anxiolytic, sedative, and hypnotic effects, whilecompounds that act as inverse agonists at this site elicit anxiogenic,cognition enhancing, and proconvulsant effects. While benzodiazepineshave enjoyed long pharmaceutical use as anxiolytics, these compounds areknown to exhibit a number of unwanted side effects. These may includecognitive impairment, sedation, ataxia, potentiation of ethanol effects,and a tendency for tolerance and drug dependence.

[0010] GABA_(A) selective ligands may also act to potentiate the effectsof certain other CNS active compounds. For example, there is evidencethat selective serotonin reuptake inhibitors (SSRIs) may show greaterantidepressant activity when used in combination with GABA_(A) selectiveligands than when used alone.

SUMMARY OF THE INVENTION

[0011] The invention provides(oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides and specifically tosuch compounds that interact with the benzodiazepine site of GABA_(A)receptors, including human GABA_(A) receptors. Preferred compounds ofthe invention interact with high selectivity and/or high affinity toGABA_(A) receptors and act as agonists, antagonists or inverse agonistsof such receptors. As such, they are useful in the treatment of avariety of CNS disorders.

[0012] In one aspect, the invention provides compounds of Formula I:

[0013] and pharmaceutically acceptable salts thereof, wherein:

[0014] n is 1, 2, or 3;

[0015] where R₁ and R₂ are independently chosen from hydrogen, halogen,hydroxy, amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; or R₁ and R₂ togetherwith the atoms with which they are attached form a partially saturatedor unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein thering is optionally substituted by up to 5 substituents independentlychosen from halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy;

[0016] R₃, R₄ and R₅ are independently chosen from (i) hydrogen; and

[0017] (ii) C₁-C₆ acyl and C₁-C₆ alkyl, each of which is optionallysubstituted with up to three substituents independently chosen fromhalogen, hydroxy, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy,C₃-C₇ cycloalkyl, phenyl, pyridyl, and pyrimidyl, wherein each ofphenyl, pyridyl, and pyrimidyl is optionally substituted with up tothree groups selected independently from halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, hydroxy and amino;

[0018] R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl;

[0019] W is aryl or heteroaryl (such as phenyl, naphthyl, pyridyl,pyrimidinyl, pyridizinyl, pyrrolyl, imidazolyl, pyrazolyl orthiophenyl), each of which is optionally substituted with up to 5 groupsindependently selected from hydrogen, halogen, hydroxy, amino, mono- ordi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl,and C₁-C₆ alkoxy.

[0020] Tn another aspect, the invention provides compounds of formulaIa:

[0021] and pharmaceutically acceptable salts thereof, wherein:

[0022] n is 1, 2, or 3;

[0023] R₁ and R₂ are independently chosen from hydrogen, halogen,hydroxy, amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; or

[0024] R₁ and R₂ together with the atoms with which they are attachedform a partially saturated or unsaturated carbocyclic ring of from 3 to8 carbon atoms, wherein the ring is optionally substituted by up to 5substituents independently chosen from halogen, hydroxy, amino, mono-and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl and C_(l)-C₆ alkoxy;

[0025] R₃, R₄ and R₅ are independently chosen from (i) hydrogen; and(ii) C₁-C₆ acyl and C₁-C₆ alkyl, each of which is optionally substitutedwith up to three substituents independently chosen from halogen,hydroxy, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇cycloalkyl, phenyl, pyridyl and pyrimidyl, wherein each of phenyl,pyridyl and pyrimidyl is optionally substituted with up to three groupsselected independently from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxyand amino;

[0026] R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl; and

[0027] R₁₀, R₁₁, X, Y and Z are independently selected from hydrogen,halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy.

[0028] In yet another aspect, the invention provides compounds offormula Ib:

[0029] and pharmaceutically acceptable salts thereof, wherein:

[0030] n is 1, 2, or 3;

[0031] R₁ and R₂ are independently chosen from hydrogen, halogen,hydroxy, amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy, or

[0032] R₁ and R₂ together with the atoms with which they are attachedform a partially saturated or unsaturated carbocyclic ring of from 3 to8 carbon atoms, wherein the ring is optionally substituted by up to 5substituents independently chosen from halogen, hydroxy, amino, mono-and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl and C₁-C₆ alkoxy;

[0033] R₃, R₄ and R₅ are independently chosen from (i) hydrogen; and

[0034] (ii) C₁-C₆ acyl and C₁-C₆ alkyl, each of which is optionallysubstituted with up to three substituents independently chosen fromhalogen, hydroxy, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy,C₃-C₇ cycloalkyl, phenyl, pyridyl and pyrimidyl, wherein each of phenyl,pyridyl and pyrimidyl is optionally substituted with up to three groupsselected independently from halogen, C₁-C₆ alkyl, C_(l)-C₆ alkoxy,hydroxy and amino;

[0035] R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl; and R₁₀, R₁₁, X, Y and Z are independentlyselected from hydrogen, halogen, hydroxy, amino, mono- anddi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyland C₁-C₆ alkoxy.

[0036] The invention also provides pharmaceutical compositionscomprising a compound or pharmaceutically acceptable salt of Formulas I,Ia, or Ib, and at least one pharmaceutically acceptable carrier, orexcipient.

[0037] The invention also provides methods for the treatment of anxiety,depression, a sleep disorder, attention deficit disorder, or Alzheimer'sdementia, comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound of FormulasI, Ia, or Ib.

[0038] The invention further provides methods for potentiating atherapeutic effect of a CNS agent, comprising administering to a patienta CNS agent and a compound of Formulas I, Ia, or Ib.

[0039] The invention further provides methods for determining thepresence or absence of GABA_(A) receptor in a sample, comprising:

[0040] (a) contacting a sample with a compound of any one of Formula I,Ia, and Ib under conditions that permit binding of the compound toGABA_(A) receptor; and

[0041] (b) detecting a level of compound bound to GABA_(A) receptor, andtherefrom determining the presence or absence of GABA_(A) receptor inthe sample.

[0042] In another aspect, the invention provides methods for making thecompounds of Formula I. And, in a related aspect, the invention providesintermediate compounds for use in methods for preparing compounds ofFormula I.

[0043] The invention further provides methods for altering thesignal-transducing activity of at least one GABA_(A) receptor,comprising contacting a cell expressing GABA_(A) receptor(s) with acompound of Formula I in an amount sufficient to detectably alter theelectrophysiology of the cell, and thereby altering GABA_(A) receptorsignal-transducing activity.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0044] Prior to setting forth the invention in detail, it may be helpfulto provide definitions of certain terms to be used herein. Compounds ofthe present invention are generally described using standardnomenclature. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E- forms, with all isomeric forms of the compounds beingincluded in the present invention. Where a compound exists in varioustautomeric forms, the invention is not limited to any one of thespecific tautomers, but rather includes all tautomeric forms.

[0045] Certain compounds are described herein using a general formulathat includes variables. Unless otherwise specified, each variablewithin such a formula is defined independently of other variable, andany variable that occurs more than one time within a formula is definedindependently at each occurrence. Thus, for example, if a group isdescribed as being substituted with 0-2 R, then the group may beunsubstituted or substituted with up to two R groups and R at eachoccurrence is selected independently from the definition of R. Inaddition, it will be apparent that combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

[0046] As used herein, “alkyl” refers to branched and straight-chainhydrocarbon groups. Preferred alkyl groups are C₁-C₆ alkyl (i.e., alkylgroups having from 1 to 6 carbon atoms). Alkyl groups of 2 or morecarbon atoms may contain double or triple bonds, which may occur at anystable point along the chain (e.g., ethynyl and propargyl). A “stablepoint” is bond that, when unsaturated, results in a chemically stablecompound (i.e., a compound that can be isolated, characterized andtested for biological activity). Examples of alkyl groups include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl and s-pentyl. An alkyl group may be bonded to an atomwithin a molecule of interest via any chemically suitable portion of thealkyl group.

[0047] As used herein, “alkoxy” represents an alkyl group as definedabove attached via an oxygen bridge. Examples of alkoxy include, but arenot limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy,neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy. “C₁-C₆alkoxy” indicates alkoxy groups having from 1 to 6 carbon atoms.

[0048] The term “aryl” is used to indicate aromatic groups that containonly carbon atoms in the ring structure. Thus, the term “aryl” refers toan aromatic hydrocarbon ring system containing at least one aromaticring. The aromatic ring may optionally be fused or otherwise attached toother aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.Examples of aryl groups are, for example, phenyl, naphthyl,1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred arylgroups include phenyl, naphthyl, including 1-naphthyl and 2-naphthyl,and acenaphthyl. More preferred aryl groups include phenyl and napthyl.The aryl groups herein are unsubstituted or, as specified, substitutedin one or more substitutable positions with various groups. Thus, sucharyl groups can be optionally substituted with, for example, C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, mono- or di(C₁-C₆)alkylamino(C₁-C₆)alkyl.

[0049] The term “halogen” includes fluorine, chlorine, bromine, andiodine.

[0050] As used herein, “haloalkyl” refers to alkyl groups (preferablysaturated aliphatic hydrocarbon groups) that are substituted with 1 ormore halogen (for example -C_(v)F_(w) where v is an integer of from 1 to3 and w is an integer of from 1 to (2v+1). Examples of haloalkyl groupsinclude, but are not limited to, mono-, di- or tri-fluoromethyl; mono-,di- or tri- chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl;and mono-, di-, tri-, tetra- or penta-chloroethyl. “Halo(C₁-C₆)alkyl”groups have 1 to 6 carbon atoms.

[0051] The term “haloalkoxy” refers to a haloalkyl group as definedabove attached via an oxygen bridge. “Halo(C₁-C₆)alkoxy” groups have 1to 6 carbon atoms. Examples of haloalkoxy groups include, but are notlimited to, trifluoromethoxy and trichloromethoxy.

[0052] As used herein, the term “heteroaryl” means stable monocyclic,bicylclic and tricyclic ring systems which contain at least one aromaticring where the aromatic ring contains from 5-7 members and from 1 to 4hetero atoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur; the remaining rings contain from 5-7members selected from carbon, oxygen, nitrogen, and sulfur. The aromaticring containing a hetero atom is the “heteroaromatic ring.” In bicyclicand tricyclic ring systems, the heteroaromatic ring may be fused to acarbocyclic ring that may be aromatic, such as benzo, or to aheteroaromatic ring, such as pyrido or pyrrolidino, or to heteroaromaticand one carbocyclic ring. Thus, “heteroaryl” includes ring systemshaving from one to three rings of from 5-7 ring members in each ring andwhere at least one ring is aromatic and contains from one to four heteroatoms. Any of the rings in the heteroaryl groups may be further fused toanother ring forming a spiro ring system.

[0053] The nitrogen and sulfur heteroatoms may optionally be oxidized.The heterocyclic ring may be attached to its pendant group at anyheteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on anysubstitutable carbon or nitrogen atom that results in a stable compound.Examples of suitable heteraryl substituents are C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- ordi-(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, amino(C₁-C₆)alkyl, and mono- ordi(C₁-C₆)alkylamino(C₁-C₆)alkyl.

[0054] Examples of heteroaryl groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0055] Preferred heteroaryl groups include, but are not limited to,pyridyl, pyrimidinyl, pyridizinyl, pyrrolyl, imidazolyl, pyrazolyl andthiophenyl.

[0056] By “C₁-C₆ acyl” herein is meant groups of the formula R_(c)C(0)—where R_(c) is alkyl of 1-5 carbon atoms.

[0057] A “carbocyclic ring” is a ring formed entirely by carbon—carbonbonds. Unless otherwise specified, such a ring may be aromatic ornon-aromatic (unsaturated, partially saturated or saturated), and isoptionally substituted. Typically, each ring contains from 3 to 8(preferably from 5 to 7) ring members. If a ring contains one or moresubstitutions, each substitution is selected independently of any othersubstitutions. Where R₁ and R₂ (together with the atoms to which theyare attached) form a partially saturated or unsaturated carbocyclic ringof from 4 to 8 carbon atoms, it is understood that the carbocyclic ringscontain at least one double bond or contain sufficient double bonds toform an aromatic carbocyclic ring. Representative examples of ringsystems resulting from R₁ and R₂ forming such a partially saturated orunsaturated carbocyclic ring (which is fused to the pyrazolopyrimidinegroup include, but are not limited to, the following structures:

[0058] A “substituent,” as used herein, refers to a molecular moietythat is covalently bonded to an atom within a molecule of interest. Forexample, a “ring substituent” may be a moiety such as a halogen, alkylgroup, alkoxy group, haloalkyl group or other group as discussed hereinthat is covalently bonded to an atom (preferably a carbon or nitrogenatom) that is a ring member. The term “substitution” refers to replacinga hydrogen atom in a molecular structure with a substituent as describedabove, such that the valence on the designated atom is not exceeded, andsuch that a chemically stable compound (i.e., a compound that can beisolated, characterized, and tested for biological activity) resultsfrom the substitution.

[0059] A dash (“-”) that is not between two letters or symbols is usedto indicate a point of attachment for a substituent. For example, —CONH₂is attached through the carbon atom.

[0060] The term “GABA_(A) receptor” refers to a protein complex thatdetectably binds GABA and mediates a dose dependent alteration inchloride conductance and membrane polarization. Receptors comprisingnaturally-occurring mammalian (especially human or rat) GABA_(A)receptor subunits are generally preferred, although subunits may bemodified provided that any modifications do not substantially inhibitthe receptor's ability to bind GABA (i.e., at least 50% of the bindingaffinity of the receptor for GABA is retained). The binding affinity ofa candidate GABA_(A) receptor for GABA may be evaluated using a standardligand binding assay as provided herein. It will be apparent that thereare a variety of GABA_(A) receptor subtypes that fall within the scopeof the term “GABA_(A) receptor.” These subtypes include, but are notlimited to, α₂β₃γ₂, α₃β₃γ₂, and α₁β₂γ₂ receptor subtypes. GABA_(A)receptors may be obtained from a variety of sources, such as frompreparations of rat cortex or from cells expressing cloned humanGABA_(A) receptors.

[0061] A “prodrug” is a compound that does not fully satisfy thestructural requirements of the compounds provided herein, but ismodified in vivo, following administration to a patient, to produce anactive compound of the present invention. For example, a prodrug may bean ester or an acylated derivative of a compound as provided herein.Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a mammalian subject,cleaves to form a free hydroxyl, amino, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups within the compounds provided herein.

[0062] A “patient” is any individual treated with a compound providedherein. Patients include humans, as well as other animals such ascompanion animals and livestock. Patients may be afflicted with a CNSdisorder, or may be free of such a condition (i.e., treatment may beprophylactic).

[0063] A “CNS disorder” is a disease or condition of the central nervoussystem that is responsive to GABA_(A) receptor modulation in thepatient. Such disorders include anxiety disorders (e.g., panic disorder,obsessive compulsive disorder, agoraphobia, social phobia, specificphobia, dysthymia, adjustment disorders, separation anxiety,cyclothymia, and generalized anxiety disorder), stress disorders (e.g.,post-traumatic stress disorder, anticipatory anxiety acute stressdisorder and acute stress disorder), depressive disorders (e.g.,depression, atypical depression, bipolar disorder and depressed phase ofbipolar disorder), sleep disorders (e.g., primary insomnia, circadianrhythm sleep disorder, dyssomnia NOS, parasomnias including nightmaredisorder, sleep terror disorder, sleep disorders secondary todepression, anxiety and/or other mental disorders and substance-inducedsleep disorder), cognitive disorders (e.g., cognition impairment, mildcognitive impairment (MCI), age-related cognitive decline (ARCD),traumatic brain injury, Down Syndrome, neurodegenerative diseases suchas Alzheimer's disease and Parkinson's disease, and stroke),AIDS-associated dementia, dementia associated with depression, anxietyor psychosis, attention deficit disorders (e.g., attention deficitdisorder and attention deficit and hyperactivity disorder), convulsivedisorders (e.g., epilepsy), benzodiazepine overdose and drug and alcoholaddiction.

[0064] A “CNS agent” is any drug used to treat or prevent a CNSdisorder. CNS agents include, for example: serotonin receptor (e.g.,5-HT_(1A)) agonists and antagonists and selective serotonin reuptakeinhibitors (SSRIs); neurokinin receptor antagonists; corticotropinreleasing factor receptor (CRF₁) antagonists; melatonin receptoragonists; nicotinic agonists; muscarinic agents; acetylcholinesteraseinhibitors and dopamine receptor agonists.

[0065] A compound is said to have “high affinity” if the K_(l) at aGABA_(A) receptor is less than 1 micromolar, preferably less than 100nanomolar or less than 10 nanomolar. A representative assay fordetermining K_(i) at GABA_(A) receptor is provided in Example 5, herein.It will be apparent that the K_(i) may depend upon the receptor subtypeused in the assay. In other words, a high affinity compound may be“subtype-specific” (i.e., the K_(l) is at least 10-fold greater for onesubtype than for another subtype). Such compounds are said to have highaffinity for GABA_(A) receptor if the K_(i) for at least one GABA_(A)receptor subtype meets the above criteria.

[0066] A compound is said to have “high selectivity” if it binds to aGABA_(A) receptor with a K_(i) that is at least 10-fold lower,preferably at least 100-fold lower, than the K_(i) for binding to othermembrane-bound receptors. In particular, the compound should have aK_(i) that is at least 10-fold greater at the following receptors thanat a GABA_(A) receptor: serotonin, dopamine, galanin, VR1, C5a, MCH,NPY, CRF, bradykinin, NK-1, NK-3 and tackykinin. Assays to determine theKi at other receptors may be performed using standard binding assayprotocols.

[0067] Preferred compounds of Formula I are those where

[0068] represents

[0069] In such preferred compounds, W is preferably heteroaryloptionally substituted with up to 5 groups independently selected fromhydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

[0070] In other such preferred compounds, W is preferably phenyloptionally substituted with up to 5 groups independently selected fromhydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

[0071] Even more preferred compounds of Formula I are those wherein:

[0072] W is pyridyl, pyrimidinyl, pyridizinyl, pyrrolyl, imidazolyl,pyrazolyl or thiophenyl, each of which is optionally substituted with upto 5 groups independently selected from hydrogen, halogen, hydroxy,amino, mono- or di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

[0073] Particularly preferred compounds are those where W is phenyl,optionally substituted with 4, or more preferably 3, groupsindependently selected from halogen, hydroxy, amino, mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, haloalkyl, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

[0074] Yet even more preferred compounds of Formula I are those wherein:

[0075] R₄ and R₅ are independently C₁-C₆ alkyl optionally substitutedwith 1 or 2 substituents independently chosen from halogen, hydroxy,trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl,phenyl, pyridyl, and pyrimidyl, wherein each of phenyl, pyridyl, andpyrimidyl is optionally substituted with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxyand amino.

[0076] More preferred compounds of Formula I are those wherein:

[0077] R₁ and R₂ are independently chosen from hydrogen, halogen,hydroxy, amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; and

[0078] R₃, R₄ and R₅ are independently C₁-C₆ alkyl.

[0079] More preferred compounds of Formula I are those wherein:

[0080] R₁ and R₂ together with the atoms with which they are attachedform a partially saturated or unsaturated carbocyclic ring of from 3 to8 carbon atoms, wherein the ring is optionally substituted by up to 5substituents independently chosen from halogen, hydroxy, amino, mono-and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl and C₁-C₆ alkoxy; and

[0081] R₃, R₄ and R₅ are independently H or C₁-C₆ alkyl.

[0082] Even more preferred compounds of Formula I are those wherein:

[0083] R₁ and R₂ together with the atoms with which they are attachedform a cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, cycloheptadienyl, phenyl, cyclooctadienyl, andcyclooctenyl, wherein each ring is optionally substituted by up to 5substituents independently chosen from halogen, hydroxy, amino, mono-and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl and C₁-C₆ alkoxy; and

[0084] R₃, R₄ and R₅ are independently C₁-C₄ alkyl.

[0085] Particularly preferred compounds of Formula I are those where R₁and R₂ are independently hydrogen or methyl, R₄ and R₅ are ethyl orpropyl, preferably n-propyl, and R₁₀, R₁₁, X, Y and Z are independentlyhydrogen, methyl, or halogen. Preferably, the phenyl group carrying R₁₀,R₁₁, X, Y and Z is phenyl substituted in the 2- and 5-positionsindependently with methyl, ethyl, or halogen, preferably chloro orfluoro, or in the 3-position with methyl, ethyl or halogen. Morepreferably, the phenyl group is substituted in the 2- and 5-positionswith halogen, preferably chloro or fluoro, or in the 3-position withhydrogen. Where phenyl is disubstituted with halogen, the halogens arepreferably the same.

[0086] Other preferred compounds of the invention include those ofFormulas II or III, wherein the variables are as defined above forFormula I:

[0087] More preferred compounds of Formulas II and III include those ofFormulas IV, V, and VI:

[0088] or a pharmaceutically acceptable salt thereof, wherein:

[0089] n, R₁, R₂, R₃, R₄, R₅, R₆ and R₆′ are as described above;

[0090] m is 1, 2 or 3;

[0091] R₁₀, R₁₁, X, Y and Z are independently selected from hydrogen,halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; and

[0092] R represents up to 5 groups independently chosen from hydrogen,halogen, hydroxy, amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl, and C₁-C₆ alkoxy.

[0093] Within Formulas IV-VI, n and m are each independently 1, 2 or 3;preferably n is 1. R₁ and R₂ are (i) are independently chosen fromhydrogen, halogen, hydroxy, amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,C₁-C₆ alkyl (preferably C₁-C₃ alkyl, more preferably methyl), and C₁-C₆alkoxy or (ii) together with the carbon atoms with which they areattached, form a partially saturated or unsaturated carbocyclic ring offrom 3 to 8 carbon atoms, wherein the ring is optionally substituted byup to three substituents independently chosen from halogen, hydroxy,amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy. Preferred R₁ and R₂groups include hydrogen, methyl, and groups that together form a 5- or6-membered optionally substituted ring.

[0094] For Formulas IV, V, and VI, R₃, R₄ and R₅ are independentlychosen from (i) hydrogen; and (ii) C₁-C₆ acyl and C₁-C₆ alkyl,optionally substituted with up to three substituents independentlychosen from halogen, hydroxy, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy,methoxy, ethoxy, C₃-C₇ cycloalkyl, phenyl, pyridyl, and pyrimidyl,wherein each of phenyl, pyridyl, and pyrimidyl is optionally substitutedwith up to three groups selected independently from halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, hydroxy and amino. Preferred R₃ groups arehydrogen, methyl and ethyl; preferred R₄ and R₅ groups are C₂-C₆ alkyland benzyl.

[0095] For Formulas IV, V, and VI, R₆ and R₆′ are independently selectedat each occurrence from hydrogen and C₁-C₆ alkyl, with hydrogen beingpreferred for certain embodiments.

[0096] For Formulas IV, V, and VI, R₁₀, R₁₁, X, Y and Z areindependently selected from hydrogen, halogen, hydroxy, amino, mono- anddi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyland C₁-C₆ alkoxy, with hydrogen, halogen, methyl and methoxy beingpreferred.

[0097] R, in Formula VI, preferably represents (i) up to four, morepreferably three, ring substituents when is 2, (ii) up to three, morepreferably 2, ring substitutuents when is 1, and (iii) up to fivesubstitutuents when is 3, where the substituents are independentlychosen from hydrogen, halogen, hydroxy, amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy.

[0098] Preferred compounds of Formula IV include those in which R₁, R₂and R₃ are independently chosen from hydrogen, methyl, and ethyl; R₄ andR₅ are independently chosen from C₂-C₆ alkyl and benzyl; R₆ and R₆′ areboth hydrogen; and R₁₀, R₁₁, X, Y and Z are independently selected fromhydrogen, halogen and methyl. More preferred compounds of Formula IV arethose where R₁ and R₂ are independently hydrogen or methyl, R₃ ismethyl, R₄ and R₅ are ethyl or propyl, preferably n-propyl, and R₁₀,R₁₁, X, Y and Z are independently hydrogen, methyl, or halogen.Preferably, the phenyl group carrying R₁₀, R₁₁, X, Y and Z is phenylsubstituted in the 2- and 5-positions independently with methyl, ethyl,or halogen, preferably chloro or fluoro, or in the 3-position withmethyl, ethyl or halogen. More preferably, the phenyl group issubstituted in the 2- and 5-positions with halogen, preferably chloro orfluoro, or in the 3-position with hydrogen. Where phenyl isdisubstituted with halogen, the halogens are preferably the same.

[0099] Preferred compounds of Formula V include those in which R₁ and R₂are independently chosen from hydrogen, methyl and ethyl; R₃ is methylor ethyl; R₆ and R₆′ are both hydrogen; and S, T, X, W, Y and Z areindependently chosen from hydrogen, halogen, methyl and methoxy.

[0100] Preferred compounds of Formula VT include those in which m is 1,and R, R₆, and R₆′ are hydrogen. Other preferred compounds of Formula VIinclude compounds where m is 1; R, R₆, and R₆′ are hydrogen; R₃ ischosen from hydrogen, methyl and ethyl; R₄ and R₅ are independentlychosen from C₂-C₆ alkyl; and R₁₀, R₁₁, X, W, Y and Z are independentlychosen from hydrogen, halogen and methyl. Still other preferredcompounds of Formula VI include those in which R₁, R₂ and R₃ areindependently chosen from hydrogen, methyl, and ethyl; R₄ and R₅ areindependently chosen from C₂-C₆ alkyl and benzyl; R₆ and R₆′ are bothhydrogen; and R₁₀, R₁₁, X, Y and Z are independently selected fromhydrogen, halogen and methyl. More preferred compounds of Formula VI arethose where R₁ and R₂ are independently hydrogen or methyl, R₃ ismethyl, R₄ and R₅ are ethyl or propyl, preferably n-propyl, and R₁₀,R₁₁, X, Y and Z are independently hydrogen, methyl, or halogen.Preferably, the phenyl group carrying R₁₀, R₁₁, X, Y and Z is phenylsubstituted in the 2- and 5-positions independently with methyl, ethyl,or halogen, preferably chloro or fluoro, or in the 3-position withmethyl, ethyl or halogen. More preferably, the phenyl group issubstituted in the 2- and 5-positions with halogen, preferably chloro orfluoro, or in the 3-position with hydrogen. Where phenyl isdisubstituted with halogen, the halogens are preferably the same.

[0101] The following numbering system is used to identify positions onthe pyrazolopyrimidine ring system of the compounds of the invention:

[0102] Representative compounds of the present invention include, butare not limited to, the compounds set forth in Tables A and I-III below,as well as the pharmaceutically acceptable acid and base addition saltsthereof.

[0103] The following representative compounds are listed to provide thereader an understanding of the compounds encompassed by the invention.

[0104]N-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0105]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0106]N-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide;

[0107]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide;

[0108] N-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide;

[0109]N-[(4-ethyl-5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0110]N-[(3-ethyl-5,6-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0111]N-[(3-ethyl-4,5,6-trimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(3-fluorophenyl)carboxamide;

[0112]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(3-fluorophenyl)carboxamide;

[0113]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(3-fluorophenyl)carboxamide;

[0114]N-[(5,6-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0115] N-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](3-fluorophenyl)carboxamide;

[0116]N-[(3-ethyl-5-methyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-chlorophenyl)carboxamide;

[0117]N-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-chlorophenyl)carboxamide;

[0118]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(3-chlorophenyl)carboxamide;

[0119]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(3-chlorophenyl)carboxamide;

[0120]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(3-chlorophenyl)carboxamide;

[0121]N-[(5,6-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide;

[0122] N-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl (4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](3-chlorophenyl)carboxamide;

[0123]N-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide;

[0124]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide;

[0125]N-ethyl-N-[(3-ethyl-5-methyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](2,5-difluorophenyl)carboxamide;

[0126]N-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide;

[0127] N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(2,5-difluorophenyl)carboxamide;

[0128]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(2,5-difluorophenyl)carboxamide;

[0129]N-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(2,5-difluorophenyl)carboxamide;

[0130]N-[(5,6-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(2,5-difluorophenyl)carboxamide;

[0131] N-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](2,5-difluorophenyl)carboxamide;

[0132]N-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide;

[0133]N-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0134]N-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide;

[0135]N-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-chlorophenyl)carboxamide;

[0136]N-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide;

[0137]N-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide;

[0138]N-[(8-oxo-3-propyl(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0139] N-[(4-methyl-8-oxo-3-propyl(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0140]N-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0141]N-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide;

[0142]N-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide;

[0143] N-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide;

[0144] N-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(2,5-difluorophenyl)carboxamide;

[0145]N-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(2,5-difluorophenyl)carboxamide;and pharmaceutically acceptable salts thereof.

[0146] It will be apparent that the specific compounds recited above areillustrative examples of compounds provided herein, and are not intendedto limit the scope of the present invention. As noted above, allcompounds of the present invention may be present as a free base or as aphysiologically acceptable acid addition salt. In addition, both chiralcompounds and racemic mixtures are encompassed by the present invention.

[0147] The present invention further provides pharmaceuticalcompositions, comprising a compound as described above in combinationwith a physiologically acceptable carrier or excipient. Thepharmaceutical composition is formulated as an injectable fluid, anaerosol, a cream, a gel, a pill, a tablet, a capsule, a syrup, or atransdermal patch. Packaged pharmaceutical compositions are alsoprovided, comprising such a pharmaceutical composition in a containerand instructions for using the composition to treat a patient sufferingfrom anxiety, depression, a sleep disorder, attention deficit disorder,or Alzheimer's dementia.

[0148] Methods are provided for the treatment of anxiety, depression, asleep disorder, attention deficit disorder, or Alzheimer's dementia,comprising administering to a patient in need of such treatment atherapeutically effective amount of a compound as described above. Thepatient may be a human or other mammal. Treatment of humans,domesticated companion animals (pets) or livestock animals sufferingfrom certain CNS disorders with an effective amount of a compound of theinvention is encompassed by the present invention.

[0149] The present invention also provides methods for potentiating atherapeutic effect of a CNS agent, comprising administering to a patienta CNS agent and a compound as described above.

[0150] Methods for determining the presence or absence of GABA_(A)receptor in a sample are further provided, comprising: (a) contacting asample with a compound as described above under conditions that permitbinding of the compound to GABA_(A) receptor; and (b) detecting a levelof compound bound to GABA_(A) receptor. Furthermore, the compounds asdescribed above can be radiolabeled, wherein the step of detectioncomprises: (i) separating unbound compound from bound compound; and (ii)detecting the presence or absence of bound compound in the sample. Whenradiolabelled compounds are used, the presence or absence of boundcompound is detected using autoradiography.

[0151] The present invention further provides a method for altering thesignal-transducing activity of GABA_(A) receptor, comprising contactinga cell expressing GABA_(A) receptor with a compound as described abovein an amount sufficient to detectably alter the electrophysiology of thecell.

[0152] More preferably, the cell recombinantly expresses a heterologousGABA_(A) receptor, wherein the alteration of the electrophysiology ofthe cell is detected by intracellular recording or patch clamprecording.

[0153] More preferably, the cell is a neuronal cell that is contacted invivo in an animal, the solution is a body fluid, and the alteration inthe electrophysiology of the cell is detected as a change in theanimal's behavior. Even more preferably the animal is a human, the cellis a brain cell, and the fluid is cerebrospinal fluid.

[0154] As noted above, the invention provides(oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides, that preferablybind with high affinity and/or high selectivity to the benzodiazepinesite of GABA_(A) receptors, including human GABA_(A) receptors.Preferably, in an assay of GABA_(A) receptor binding, the abovecompounds exhibit an K_(i) of 1 micromolar or less. More preferably, inan assay of GABA_(A) receptor binding, the compound exhibits an K_(i) of100 nanomolar or less. Even more preferably, in an assay of GABA_(A)receptor binding, the compound exhibits an K_(i) of 10 nanomolar orless.

[0155] The above compounds are also useful for the manufacture of amedicament for the treatment of anxiety, depression, a sleep disorder,an attention deficit disorder, or Alzheimer's dementia.

[0156] Without wishing to be bound to any particular theory, it isbelieved that the interaction of the compounds provided herein with thebenzodiazepine site results in the pharmaceutical utility of thesecompounds. Compounds provided herein may be used in a variety of in vivoand in vitro contexts, as discussed in further detail below.

[0157] The compounds provided herein detectably alter (modulate) ligandbinding to GABA_(A) receptor, as determined using a standard in vitroreceptor binding assay. References herein to a “GABA_(A) receptor ligandbinding assay” are intended to refer to the standard in vitro receptorbinding assay provided in Example 5. Briefly, a competition assay may beperformed in which a GABA_(A) receptor preparation is incubated withlabeled (e.g., ³H) ligand, such as Flumazenil, and unlabeled testcompound. Incubation with a compound that detectably modulates ligandbinding to GABA_(A) receptor will result in a decrease or increase inthe amount of label bound to the GABA_(A) receptor preparation, relativeto the amount of label bound in the absence of the compound. Preferably,such a compound will exhibit a K_(i) at a GABA_(A) receptor of less than1 micromolar, more preferably less than 500 nM, 100 nM, 20 nM or 10 nM.The GABA_(A) receptor used to determine in vitro binding may be obtainedfrom a variety of sources, for example from preparations of rat cortexor from cells expressing cloned human GABA_(A) receptors.

[0158] If desired, compounds provided herein may be evaluated forcertain pharmacological properties including, but not limited to,solubility, oral bioavailability, toxicity, serum protein binding, lackof clinically relevant EKG effect and in vitro and in vivo half-life.Routine assays that are well known in the art may be used to assessthese properties, and identify superior compounds for a particular use.For example, solubility in aqueous solutions is preferably at least 500ng/mL. Assays used to predict bioavailability include transport acrosshuman intestinal cell monolayers, including Caco-2 cell monolayers.Toxicity may be assessed using any standard method, such as the assaydetecting an effect on cellular ATP production provided in Example 7, ortoxicity to cultured hepatocytes. Penetration of the blood brain barrierof a compound in humans may be predicted from the brain levels of thecompound in laboratory animals given the compound intravenously. Serumprotein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27). Compound half-life isinversely proportional to the frequency of dosage of a compound. Invitro half-lives of compounds may be predicted from assays of microsomalhalf-life as described by Kuhnz and Gieschen (Drug Metabolism andDisposition, (1998) volume 26, pages 1120-1127).

[0159] For detection purposes, as discussed in more detail below,compounds provided herein may be isotopically-labeled or radiolabeled.Such compounds are identical to those described above, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsprovided herein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸O ,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. In addition, substitution withheavy isotopes such as deuterium (i.e., ²H) can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances.

Preparation of Compounds

[0160] Compounds provided herein may generally be prepared usingstandard synthetic methods. Starting materials are generally readilyavailable from commercial sources, such as Sigma-Aldrich Corp. (St.Louis, Mo.). A representative route suitable for preparing compounds ofthe invention is shown in Scheme I. In addition, other synthetic routessimilar to that shown in Scheme I may be used. Within Scheme I, thesubstituents R₁, R₂, R₃, R₄, R₅, R₁₀, R₁₁, X, Y and Z carry thedefinitions set forth above.

[0161] It will be apparent that the starting materials may be varied andadditional steps employed to produce the varied compounds encompassed bythe present invention. In some cases, protection of reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general, such need for protecting groups, as well asthe conditions necessary to attach and remove such groups, will beapparent to those skilled in the art of organic synthesis.

[0162] In certain situations, compounds provided herein may contain oneor more asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. As noted above, all stereoisomersare encompassed by the present invention. Nonetheless, it may bedesirable to obtain single enantiomers (i.e., optically active forms).Standard methods for preparing single enantiomers include asymmetricsynthesis and resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatographyusing, for example a chiral HPLC column.

[0163] As noted above, the present invention encompassespharmaceutically acceptable salts of the compounds described herein. Asused herein, a “pharmaceutically acceptable salt” is an acid or basesalt that is generally considered in the art to be suitable for use incontact with the tissues of human beings or animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication. Such salts include mineral and organic acid salts of basicresidues such as amines, as well as alkali or organic salts of acidicresidues such as carboxylic acids. Specific pharmaceutical saltsinclude, but are not limited to, salts of acids such as hydrochloric,phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic,sulfanilic, formic, toluenesulfonic, methanesulfonic, ethane disulfonic,2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric,tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic,succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic,phenylacetic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where n is0-4, and the like. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those of ordinary skill in the art will recognizefurther pharmaceutically acceptable salts for the compounds providedherein, including those listed by Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).Accordingly, the present disclosure should be construed to include allpharmaceutically acceptable salts of the compounds specifically recited.

[0164] A wide variety of synthetic procedures are available for thepreparation of pharmaceutically acceptable salts. In general, apharmaceutically acceptable salt can be synthesized from a parentcompound that contains a basic or acidic moiety by any conventionalchemical method. Briefly, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred.

[0165] Prodrugs of the compounds provided herein may be prepared bymodifying functional groups present in the compounds in such a way thatthe modifications are cleaved to the parent compounds. Prodrugs includecompounds wherein hydroxy, amine or sulfhydryl groups are bonded to anygroup that, when administered to a mammalian subject, cleaves to form afree hydroxyl, amino, or sulfhydryl group, respectively. Examples ofprodrugs include, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups within the compoundsprovided herein. Preferred prodrugs include acylated derivatives. Thoseof ordinary skill in the art will recognize various synthetic methodsthat may be employed to prepare prodrugs of the compounds providedherein.

[0166] Compounds may be radiolabeled by carrying out their synthesisusing precursors comprising at least one atom that is a radioisotope.Such radioisotope(s) are preferably selected from carbon (preferably¹⁴C), hydrogen (preferably ³H), sulfur (preferably ³⁵S), or iodine(preferably ¹²⁵I). Synthesis of such radiolabeled compounds may beconveniently performed by a radioisotope supplier specializing in customsynthesis of radiolabeled probe compounds, such as Amersham Corporation,Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover,Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, WestSacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; AmericanRadiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek BiochemicalsInc., Brea, Calif. Tritium labeled compounds are also convenientlyprepared catalytically via platinum-catalyzed exchange in tritiatedacetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid,or heterogeneous-catalyzed exchange with tritium gas. Such preparationsare also conveniently carried out as a custom radiolabeling by any ofthe suppliers listed above using the compound as substrate. In addition,certain precursors may be subjected to tritium-halogen exchange withtritium gas, tritium gas reduction of unsaturated bonds, or reductionusing sodium borotritide, as appropriate. ¹⁴C radiolabeled compounds ofthe invention may be prepared using ¹⁴C radiolabeled diethyl oxalate(AMERICAN RADIOLABELED CHEMICALS, St. Louis, Mo., catalog no. ARC-1127)as a starting material for the synthesis outlined in Scheme I.

Pharmaceutical Compositions

[0167] The present invention also provides pharmaceutical compositionscomprising at least one compound provided herein, together with at leastone physiologically acceptable carrier or excipient. Such compounds maybe used for treating disorders responsive to GABA_(A) receptormodulation (e.g., treatment of anxiety, depression, sleep disorders orcognitive impairment by GABA_(A) receptor modulation). Pharmaceuticalcompositions may comprise, for example, water, buffers (e.g., neutralbuffered saline or phosphate buffered saline), ethanol, mineral oil,vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose,sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides oramino acids such as glycine, antioxidants, chelating agents such as EDTAor glutathione and/or preservatives. Preferred pharmaceuticalcompositions are formulated for oral delivery to humans or other animals(e.g., companion animals such as dogs). If desired, other activeingredients may also be included, such as CNS agents.

[0168] Pharmaceutical compositions may be formulated for any appropriatemanner of administration, including, for example, topical, oral, nasal,rectal or parenteral administration. The term parenteral as used hereinincludes subcutaneous, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intracranial, intrathecal and intraperitonealinjection, as well as any similar injection or infusion technique. Incertain embodiments, compositions in a form suitable for oral use arepreferred. Such forms include, for example, tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Within yet otherembodiments, compositions of the present invention may be formulated asa lyophilizate.

[0169] Compositions intended for oral use may further comprise one ormore components such as sweetening agents, flavoring agents, coloringagents and preserving agents in order to provide appealing and palatablepreparations. Tablets contain the active ingredient in admixture withphysiologically acceptable excipients that are suitable for themanufacture of tablets. Such excipients include, for example, inertdiluents (e.g., calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate), granulating and disintegrating agents(e.g., corn starch or alginic acid), binding agents (e.g., starch,gelatin or acacia) and lubricating agents (e.g., magnesium stearate,stearic acid or talc). The tablets may be uncoated or they may be coatedby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0170] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent (e.g., calcium carbonate, calcium phosphate or kaolin), or assoft gelatin capsules wherein the active ingredient is mixed with wateror an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0171] Aqueous suspensions comprise the active materials in admixturewith one or more excipients suitable for the manufacture of aqueoussuspensions. Such excipients are suspending agents (e.g., sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia);and dispersing or wetting agents (e.g., naturally-occurring phosphatidessuch as lecithin, condensation products of an alkylene oxide with fattyacids such as polyoxyethylene stearate, condensation products ofethylene oxide with long chain aliphatic alcohols such asheptadecaethyleneoxycetanol, condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides such as polyethylene sorbitan monooleate). Aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

[0172] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oilor coconut oil) or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and/or flavoring agents may be added to provide palatable oralpreparations. Such suspension may be preserved by the addition of ananti-oxidant such as ascorbic acid.

[0173] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, such as sweetening, flavoring and coloringagents, may also be present.

[0174] Pharmaceutical compositions may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil (e.g.,olive oil or arachis oil) or a mineral oil (e.g., liquid paraffin) ormixtures thereof. Suitable emulsifying agents may be naturally-occurringgums (e.g., gum acacia or gum tragacanth), naturally-occurringphosphatides (e.g., soy bean, lecithin, and esters or partial estersderived from fatty acids and hexitol), anhydrides (e.g., sorbitanmonoleate) and condensation products of partial esters derived fromfatty acids and hexitol with ethylene oxide (e.g., polyoxyethylenesorbitan monoleate). The emulsions may also contain sweetening and/orflavoring agents.

[0175] Syrups and elixirs may be formulated with sweetening agents, suchas glycerol, propylene glycol, sorbitol or sucrose. Such formulationsmay also comprise one or more demulcents, preservatives, flavoringagents and/or coloring agents.

[0176] A pharmaceutical composition may be prepared as a sterileinjectible aqueous or oleaginous suspension. The compound, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Such a composition may be formulated according to theknown art using suitable dispersing, wetting agents and/or suspendingagents such as those mentioned above. Among the acceptable vehicles andsolvents that may be employed are water, 1,3-butanediol, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils may be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectable compositions, and adjuvants such as localanesthetics, preservatives and/or buffering agents can be dissolved inthe vehicle.

[0177] Pharmaceutical compositions may also be prepared in the form ofsuppositories (e.g., for rectal administration). Such compositions canbe prepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Suitable excipients include, for example, cocoa butter and polyethyleneglycols.

[0178] For administration to non-human animals, the composition may alsobe added to animal feed or drinking water. It may be convenient toformulate animal feed and drinking water compositions so that the animaltakes in an appropriate quantity of the composition along with its diet.It may also be convenient to present the composition as a premix foraddition to feed or drinking water.

[0179] Pharmaceutical compositions may be formulated as sustainedrelease formulations (i.e., a formulation such as a capsule that effectsa slow release of compound following administration). Such formulationsmay generally be prepared using well known technology and administeredby, for example, oral, rectal or subcutaneous implantation, or byimplantation at the desired target site. Carriers for use within suchformulations are biocompatible, and may also be biodegradable;preferably the formulation provides a relatively constant level ofactive compound release. The amount of compound contained within asustained release formulation depends upon the site of implantation, therate and expected duration of release and the nature of the condition tobe treated or prevented.

[0180] Compounds provided herein are generally present within apharmaceutical composition in a therapeutically effective amount. Atherapeutically effective amount is an amount that results in adiscernible patient benefit, such as diminution of symptoms of a CNSdisorder. A preferred concentration is one sufficient to inhibit thebinding of GABA_(A) receptor ligand to GABA_(A) receptor in vitro.Compositions providing dosage levels ranging from about 0.1 mg to about140 mg per kilogram of body weight per day are preferred (about 0.5 mgto about 7 g per human patient per day). The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. Dosage unit forms will generally contain betweenfrom about 1 mg to about 500 mg of an active ingredient. It will beunderstood, however, that the optimal dose for any particular patientwill depend upon a variety of factors, including the activity of thespecific compound employed; the age, body weight, general health, sexand diet of the patient; the time and route of administration; the rateof excretion; any simultaneous treatment, such as a drug combination;and the type and severity of the particular disease undergoingtreatment. Optimal dosages may be established using routine testing, andprocedures that are well known in the art.

[0181] Pharmaceutical compositions may be packaged for treating a CNSdisorder such as anxiety, depression, a sleep disorder, attentiondeficit disorder or Alzheimer's dementia. Packaged pharmaceuticalcompositions include a container holding a therapeutically effectiveamount of at least one compound as described herein and instructions(e.g., labeling) indicating that the contained composition is to be usedfor treating the CNS disorder.

Methods of Use

[0182] Within certain aspects, the present invention provides methodsfor inhibiting the development of a CNS disorder. In other words,therapeutic methods provided herein may be used to treat a disorder, ormay be used to prevent or delay the onset of such a disease in a patientwho is free of detectable CNS disorder. CNS disorders are discussed inmore detail below, and may be diagnosed and monitored using criteriathat have been established in the art. Patients may include humans,domesticated companion animals (pets, such as dogs) and livestockanimals, with dosages and treatment regimes as described above.

[0183] Frequency of dosage may vary depending on the compound used andthe particular disease to be treated or prevented. In general, fortreatment of most disorders, a dosage regimen of 4 times daily or lessis preferred. For the treatment of sleep disorders a single dose thatrapidly reaches effective concentrations is desirable. Patients maygenerally be monitored for therapeutic effectiveness using assayssuitable for the condition being treated or prevented, which will befamiliar to those of ordinary skill in the art.

[0184] Within preferred embodiments, compounds provided herein are usedto treat patients in need of such treatment, in an amount sufficient toalter the symptoms of a CNS disorder. Compounds that act as agonists atα₂β₃γ₂ and α₃β₃γ₂ receptor subtypes are particularly useful in treatinganxiety disorders such as panic disorder, obsessive compulsive disorderand generalized anxiety disorder; stress disorders includingpost-traumatic stress, and acute stress disorders. Compounds that act asagonists at α₂β₃γ₂ and α₃β₃γ₂ receptor subtypes are also useful intreating depressive or bipolar disorders and in treating sleepdisorders. Compounds that act as inverse agonists at the α₅β₃γ₂ receptorsubtype or α₁β₂γ₂ and α₅β₃γ₂ receptor subtypes are particularly usefulin treating cognitive disorders including those resulting from DownSyndrome, neurodegenerative diseases such as Alzheimer's disease andParkinson's disease, and stroke related dementia. Compounds of theinvention that act as inverse agonists at the α₅β₃γ₂ are particularlyuseful in treating cognitive disorders through the enhancement ofmemory, and particularly short-term memory, in memory-impaired patients.Compounds that act as agonists at the α₁β₂γ₂ receptor subtype are usefulin treating convulsive disorders such as epilepsy. Compounds that act asantagonists at the benzodiazepine site are useful in reversing theeffect of benzodiazepine overdose and in treating drug and alcoholaddiction.

[0185] CNS disorders that can be treated using compounds andcompositions provided herein include:

[0186] Depression, e.g., depression, atypical depression, bipolardisorder, depressed phase of bipolar disorder.

[0187] Anxiety, e.g., general anxiety disorder (GAD), agoraphobia, panicdisorder +/− agoraphobia, social phobia, specific phobia, Post traumaticstress disorder, obsessive compulsive disorder (OCD), dysthymia,adjustment disorders with disturbance of mood and anxiety, separationanxiety disorder, anticipatory anxiety acute stress disorder, adjustmentdisorders, cyclothymia.

[0188] Sleep disorders, e.g., sleep disorders including primaryinsomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias,including nightmare disorder, sleep terror disorder, sleep disorderssecondary to depression and/or anxiety or other mental disorders,substance induced sleep disorder.

[0189] Cognition Impairment, e.g., cognition impairment, Alzheimer'sdisease, Parkinson's disease, mild cognitive impairment (MCI),age-related cognitive decline (ARCD), stroke, traumatic brain injury,AIDS associated dementia, and dementia associated with depression,anxiety or psychosis.

[0190] Attention Deficit Disorder, e.g., attention deficit disorder(ADD), and attention deficit and hyperactivity disorder (ADHD).

[0191] In a separate aspect, the present invention provides methods forpotentiating the action (or therapeutic effect) of other CNS agent(s).Such methods comprise administering an effective amount of a compoundprovided herein in combination with another CNS agent. Such CNS agentsinclude, but are not limited to the following: for anxiety, serotoninreceptor (e.g., 5-HT_(1A)) agonists and antagonists; for anxiety anddepression, neurokinin receptor antagonists or corticotropin releasingfactor receptor (CRF₁) antagonists; for sleep disorders, melatoninreceptor agonists; and for neurodegenerative disorders, such asAlzheimer's dementia, nicotinic agonists, muscarinic agents,acetylcholinesterase inhibitors and dopamine receptor agonists. Withinpreferred embodiments, the present invention provides a method ofpotentiating the antidepressant activity of selective serotonin reuptakeinhibitors (SSRIs) by administering an effective amount of a GABAagonist compound of the invention in combination with an SSRI. Aneffective amount of compound is an amount sufficient to result in adetectable change in patient symptoms, when compared to a patienttreated with the other CNS agent alone.

[0192] Combination administration can be carried out in a fashionanalogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology(1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10)1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132.See also the discussion of the use of the GABA_(A) receptor ligand3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazinein combination with nicotinic agonists, muscarinic agonists and Inaddition, WO 99/37303 describes the use of a class of GABA_(A) receptorligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.

[0193] The present invention also pertains to methods of inhibiting thebinding of benzodiazepine compounds, such as Ro15-1788, or GABA to theGABA_(A) receptors. Such methods involve contacting a compound providedherein with cells expressing GABA_(A) receptor, wherein the compound ispresent in an amount sufficient to inhibit benzodiazepine binding orGABA binding to GABA_(A) receptors in vitro. This method includesinhibiting the binding of benzodiazepine compounds to GABA_(A) receptorsin vivo (e.g., in a patient given an amount of a compound providedherein that would be sufficient to inhibit the binding of benzodiazepinecompounds or GABA to GABA_(A) receptors in vitro). In one embodiment,such methods are useful in treating benzodiazepine drug overdose. Theamount of a compound that would be sufficient to inhibit the binding ofa benzodiazepine compound to the GABA_(A) receptor may be readilydetermined via an GABA_(A) receptor binding assay, such as the assaydescribed in Example 5.

[0194] Within separate aspects, the present invention provides a varietyof in vitro uses for the compounds provided herein. For example, suchcompounds may be used as probes for the detection and localization ofGABA_(A) receptors, in samples such as tissue sections, as positivecontrols in assays for receptor activity, as standards and reagents fordetermining the ability of a candidate agent to bind to GABA_(A)receptor, or as radiotracers for positron emission tomography (PET)imaging or for single photon emission computerized tomography (SPECT).Such assays can be used to characterize GABA_(A) receptors in livingsubjects. Such compounds are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind toGABA_(A) receptor.

[0195] Within methods for determining the presence or absence ofGABA_(A) receptor in a sample, a sample may be incubated with a compoundas provided herein under conditions that permit binding of the compoundto GABA_(A) receptor. The amount of compound bound to GABA_(A) receptorin the sample is then detected. For example, a compound may be labeledusing any of a variety of well known techniques (e.g., radiolabeled witha radionuclide such as tritium, as described herein), and incubated withthe sample (which may be, for example, a preparation of cultured cells,a tissue preparation or a fraction thereof). A suitable incubation timemay generally be determined by assaying the level of binding that occursover a period of time. Following incubation, unbound compound isremoved, and bound compound detected using any method for the labelemployed (e.g., autoradiography or scintillation counting forradiolabeled compounds; spectroscopic methods may be used to detectluminescent groups and fluorescent groups). As a control, a matchedsample may be simultaneously contacted with radiolabeled compound and agreater amount of unlabeled compound. Unbound labeled and unlabeledcompound is then removed in the same fashion, and bound label isdetected. A greater amount of detectable label in the test sample thanin the control indicates the presence of capsaicin receptor in thesample. Detection assays, including receptor autoradiography (receptormapping) of GABA_(A) receptors in cultured cells or tissue samples maybe performed as described by Kuhar in sections 8.1.1 to 8.1.9 of CurrentProtocols in Pharmacology (1998) John Wiley & Sons, New York.

[0196] Compounds provided herein may also be used within a variety ofwell known cell culture and cell separation methods. For example,compounds may be linked to the interior surface of a tissue cultureplate or other cell culture support, for use in immobilizing GABA_(A)receptor-expressing cells for screens, assays and growth in culture.Such linkage may be performed by any suitable technique, such as themethods described above, as well as other standard techniques. Compoundsmay also be used to facilitate cell identification and sorting in vitro,permitting the selection of cells expressing a GABA_(A) receptor.Preferably, the compound(s) for use in such methods are labeled asdescribed herein. Within one preferred embodiment, a compound linked toa fluorescent marker, such as fluorescein, is contacted with the cells,which are then analyzed by fluorescence activated cell sorting (FACS).

[0197] Within other aspects, methods are provided for modulating bindingof ligand to a GABA_(A) receptor in vitro or in vivo, comprisingcontacting a GABA_(A) receptor with a sufficient amount of a compoundprovided herein, under conditions suitable for binding of ligand to thereceptor. The GABA_(A) receptor may be present in solution, in acultured or isolated cell preparation or within a patient. Preferably,the GABA_(A) receptor is a present in the brain of a mammal. In general,the amount of compound contacted with the receptor should be sufficientto modulate ligand binding to GABA_(A) receptor in vitro within, forexample, a binding assay as described in Example 5.

[0198] Also provided herein are methods for altering thesignal-transducing activity of cellular GABA_(A) receptor (particularlythe chloride ion conductance), by contacting GABA_(A) receptor, eitherin vitro or in vivo, with a sufficient amount of a compound as describedabove, under conditions suitable for binding of ligand to the receptor.The GABA_(A) receptor may be present in solution, in a cultured orisolated cell preparation or within a patient. In general, the amount ofcompound contacted with the receptor should be sufficient to modulateligand binding to GABA_(A) receptor in vitro within, for example, abinding assay as described in Example 5. An effect on signal-transducingactivity may be assessed as an alteration in the electrophysiology ofthe cells, using standard techniques. Tf the receptor is present in ananimal, an alteration in the electrophysiology of the cell may bedetected as a change in the animal's feeding behavior. The amount of acompound that would be sufficient to alter the signal-transducingactivity of GABA_(A) receptors may be determined via a GABA_(A) receptorsignal transduction assay, such as the assay described in Example 6. Thecells expressing the GABA receptors in vivo may be, but are not limitedto, neuronal cells or brain cells. Such cells may be contacted withcompounds of the invention through contact with a body fluid containingthe compound, for example through contact with cerebrospinal fluid.Alteration of the signal-transducing activity of GABA_(A) receptors invitro may be determined from a detectable change in theelectrophysiology of cells expressing GABA_(A) receptors, when suchcells are contacted with a compound of the invention in the presence ofGABA.

[0199] Intracellular recording or patch-clamp recording may be used toquantitate changes in electrophysiology of cells. A reproducible changein behavior of an animal given a compound of the invention may also beused to indicate that changes in the electrophysiology of the animal'scells expressing GABA_(A) receptors has occurred.

[0200] The following Examples are offered by way of illustration and notby way of limitation. Unless otherwise specified all reagents andsolvent are of standard commercial grade and are used without furtherpurification.

EXAMPLES Example 1 Preparation of Starting Materials and Intermediates

[0201] The starting materials and various intermediates may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.Representative examples of methods for preparing intermediates of theinvention are set forth below.

A. Preparation of ethyl 5-amino-4-propylpyrazolo-3-carboxylate

[0202]

[0203] 144 mL of 2M lithium diisopropylamide inheptane/tetrahydrofuran/ethylbenzene at −78° C. is added to a solutionof 20 g valeronitrile in 50 mL of tetrahydrofuran. The mixture isstirred at −78° C. for 1 hour, and then added to a solution of 35.2 g ofdiethyloxalate in 100 mL of tetrahydrofuran. The resulting solution isstirred at −78° C. for 3 hours. The reaction is quenched by addition ofaqueous NH₄Cl solution followed by 3N HCl. The reaction mixture istransferred to a separatory funnel and extracted with ethyl acetate. Theorganic layer is washed with brine, dried over sodium sulfate, filtered,and evaporated to give a brown oil. The oil, 23.3 g of hydrazinemonohydrate, 43 mL of acetic acid and 430 mL of toluene are refluxedovernight using a Dean Stark trap. The solvent is removed in vacuo, andthe residue partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic layer is dried over sodium sulfate andfiltered. The solvent is removed in vacuo, and the residue is purifiedby silica gel column chromatography eluting with ethylacetate:hexanes=1:1 to give 12.1 g of the title compound as an off-whitesolid. ¹H NMR (CDCl₃) δ: 0.95 (t, 3H), 1.38 (t, 3H) , 1.55 (m, 2H) ,2.58 (t, 2H), 4.36 (q, 2H). LC-MS (APCI, m/z) 198 (M+1).

B. Preparation of ethyl5-methyl-3-propyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate

[0204]

[0205] A mixture of 11.5 g of ethyl5-amino-4-propylpyrazole-3-carboxylate, 11.3 g of ethyl acetoacetate,and 100 mL of acetic acid is refluxed overnight. The solvent is removedin vacuo, and the residue triturated with hexane/ether (1:1) to give14.8 g of off-white solid. ¹H NMR (CD₃OD) δ: 0.97 (t, 3H), 1.40 (t, 3H),1.61 (m, 2H), 2.42 (s, 3H), 2.85 (t, 2H), 4.40 (q, 2H), 5.73 (s, 1H).LC-MS (APCI, m/z): 264 (M+1).

C. Preparation of2-(hydroxymethyl)-5-methyl-3-propyl-4,7-dihydropyrazolo[1,5a]pyrimidin-7-one

[0206]

[0207] To a solution of 14.8 g of ethyl5-methyl-7-oxo-3-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylatein 600 mL of tetrahydrofuran, is added 67.5 mL of 1 M lithium aluminumhydride in tetrahydrofuran. The reaction mixture is stirred for 1 hourat 0° C. then quenched with sodium carbonate decahydrate and filteredthrough Celite. The filtrate is concentrated in vacuo to give 10.9 g ofyellow solid. ¹H NMR (CD₃OD) δ: 0.96 (t, 3H), 1.62 (m, 2H), 2.38 (s,3H), 2.65 (t, 2H), 4.65 (s, 2H), 5.62 (s, 1H). LC-MS (APCI, m/z): 222(M+1).

D. Preparation of5-methyl-3-propyl-2-[(propylamino)methyl]-4,7-dihydropyrazolo[1,5a]pyrimidin-7-one

[0208]

[0209] 1.4 g of methanesulfonyl chloride is added to a solution of 1.6 gof2-(hydroxymethyl)-5-methyl-3-propyl-4,7a-dihydropyrazolo[1,5a]pyrimidin-7-onein 70 mL of chloroform, 10 mL of N,N-dimethylformamide and 1.8 mL oftriethylamine. The reaction mixture is stirred at 0° C. for 2 hours. Thesolution is then added to 20 mL propylamine and stirred at roomtemperature overnight. The solvent is removed in vacuo, and the residuepurified by silica gel chromatography eluting withCHCl₃:MeOH:TEA=90:10:1 to give 0.91 g of the title compound as a yellowsolid. ¹H NMR (CD₃OD) δ: 0.80 (br s, 3H), 0.95 (t, 3H), 1.40 (br s, 2H),1.68 (m, 2H), 2.33 (s, 3H), 2.54 (br s, 2H), 2.93 (t, 2H), 4.27 (s, 2H),5.76 (s, 1H). LC-MS (APCI, m/z) : 263 (M+1).

Example 2 Preparation ofN-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide

[0210]

[0211] To a solution of 0.6 g of5-methyl-3-propyl-2-[(propylamino)methyl]-4,7-dihydropyrazolo[1,5a]pyrimidin-7-onein 10 mL of CHCl₃ and 1 mL of TEA is added 0.55 g of 3-fluorobenzoylchloride in 17 mL of toluene. The reaction mixture is stirred at roomtemperature for 3 hours. The reaction is quenched by the addition ofwater then transferred to a separatory funnel. The organic layer iswashed with brine, dried over sodium sulfate, and filtered. The solventis removed in vacuo and the residue purified by silica gelchromatography and eluted with EA:MeOH:TEA=10:2:1 to give 0.67 g of thetitle compound as a yellow solid. ¹H NMR data listed in table 1. LC-MS(APCI, m/z): 385 (M+1).

Example 3 Preparation ofN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamideandN-[(7-methoxy-5-methyl-3-propyl(7a-hydropyrazolo[1,5a]pyrimidin-2yl))methyll-N-propyl(3-fluorophenyl)carboxamide

[0212]

[0213] 72.4 mg of iodomethane is added to a solution of 130 mg ofN-[(5-methyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide and 70.4 mg of potassium carbonate in 5 mL ofN,N-dimethylformamide. The reaction mixture is stirred at roomtemperature overnight. The reaction mixture is diluted with ethylacetate, washed with water and brine, dried over sodium sulfate, andfiltered. The solvent is removed in vacuo and the residue purified bypreparative TLC, eluting with CH₂Cl₂:MeOH=9:1 to give 60 mg ofN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamideas a yellow oil and 50 mg ofN-[(7-methoxy-5-methyl-3-propyl(7a-hydropyrazolo[1,5a]pyrimidin-2yl))methyl]-N-propyl(3-fluorophenyl)carboxamide as an off-white solid). ¹H NMR data are listed in TablesI-III respectively. LC-MS (APCT, m/z): 399 (M+1).

Example 4

[0214] The following compounds (Table I, II and III) are preparedessentially according to the procedures described above. Most of thecompounds exist as mixtures of rotamers, H and H′ denote major and minorforms respectively. TABLE 1

No. R1 R2 R3 R4 R5 X Name ¹H NMR (CDCl_(3]l ) δ) H/H′ 1 H CH₃ H PropylPropyl 3-Fluoro N-[(5-methyl-7-oxo-3- 0.60-0.90 (m, 6H + 6H′), 1.40-1.604/1 propyl (4,7- (m, 4H + 4H′), 2.20-2.63 (m, 5H + dihydropyrazolo[1,5a]pyrimidin- 5H′), 3.16 (t, 2H), 3.36 (br s, 2-yl))methyl]-N- 2H′),4.73 (s, 2H), 4.53 (s, 2H′), propyl (3- 5.51 (s, 1H), 5.53 (s, 1H′),7.03- fluorophenyl)carboxamide 7.37 (m, 4H + 4H′) 2 H CH₃ CH₃ PropylPropyl 3-Fluoro N-[(4,5-dimethyl-7-oxo-3- 0.67 (t, 3H), 0.84 (br s,3H′), 1.04 4/1 propyl (4,7- (t, 3H), 0.91 (br s, 3H′), 1.30-1.70dihydropyrazolo[1,5a]pyrimidin- (m, 4H + 4H′), 2.39 (s, 3H), 2.362-yl))methyl]-N- (s, 3H′), 2.80 (t, 2H), 2.43 (br s, propyl (3- 2H′),3.20 (t, 2H), 3.42 (br s, fluorophenyl)carboxamide 2H′), 3.80 (s, 3H),3.75 (s, 3H′), 4.95 (s, 2H), 4.64 (s, 2H′), 5.73 (s, 1H + 1H′),7.04-7.44 (m, 4H + 4H′) 3 H CH₃ H Propyl isobutyl 3-FluoroN-[(5-methyl-7-oxo-3- 0.60-0.87 (m, 9H + 9H′), 1.46 (br 3/1 propyl (4,7-s, 2H + 2H′), 1.98 (m, 1H + 1H′), dihydropyrazolo[1,5a]pyrimidin-2.08-2.60 (m, 5H + 5H′), 3.09 (d, 2-yl))methyl]-N-(2- 2H), 3.20 (d,2H′), 4.81 (s, 2H), methylpropyl)(3- 4.56 (s, 2H′), 5.56 (s, 1H), 5.63fluorophenyl)carboxamide (s, 1H′), 7.01-7.39 (m, 4H + 4H′) 4 H CH₃ CH₃Propyl isobutyl 3-Fluoro N-[(4,5-dimethyl-7-oxo-3- 0.69 (d, 6H), 0.96(d, 6H′), 0.85 3/1 propyl (4,7- (t, 3H), 1.02 (t, 3H′), 1.57 (m, 2H +dihydropyrazolo[1,5a]pyrimidin- 2H′), 2.16 (m, 1H + 1H′), 2.382-yl))methyl]-N-(2- (s, 3H + 3H′), 2.80 (t, 2H + 2H′), methylpropyl)(3-3.09 (d, 2H), 3.25 (d, 2H′), 3.80 fluorophenyl)carboxamide (s, 3H), 3.73(s, 3H′), 4.92 (s, 2H), 4.65 (s, 2H′), 5.75 (s, 1H + 1H′), 7.04-7.41 (m,4H + 4H′) 5 H CH₃ CH₃ Ethyl isobutyl 3-FluoroN-[(3-ethyl-4,5-dimethyl-7- 0.71 (d, 6H), 0.91 (d, 6H′), 1.25 3/1 oxo(4,7- (t, 3H), 1.04 (t, 3H′), 2.16 (m, 1H +dihydropyrazolo[1,5a]pyrimidin- 1H′), 2.35 (s, 3H + 3H′), 2.852-yl))methyl]-N-(2- (q, 2H), 2.47 (q, 2H′), 3.08 (d, methylpropyl)(3-2H), 3.23 (d, 2H′), 3.08 (d, fluorophenyl)carboxamide 3.71 (s, 3H′),4.93 (s, 2H), 4.64 (s, 2H′), 5.69 (s, 1H + 1H′), 7.04- 7.43 (m, 4H +4H′) 6 H CH₃ Ethyl Propyl Propyl 3-Fluoro N-[(4-ethyl-5-methyl-7-oxo-0.69 (t, 3H), 0.83 (m, 3H′), 1.05 3/1 3-propyl(4,7- (t, 3H), 0.94 (m,3H′), 1.38 (t, 3H + dihydropyrazolo[1,5a]pyrimidin- 3H′), 1.47-1.70 (m,4H + 4H′), 2-yl))methyl]-N- 2.42 (s, 3H + 3H′), 2.69 (t, 2H), propyl(3-2.31 (br s, 2H′), 3.22 (t, 2H), fluorophenyl)carboxamide 3.44 (br s,2H′), 4.15 (q, 2H), 4.04 (br s, 2H′), 4.96 (s, 2H), 4.65 (s, 2H′), 5.76(s, 1H + 1H′), 7.05-7.41 (m, 4H + 4H′) 7 CH₃ CH₃ H Ethyl Propyl 3-FluoroN-[(3-ethyl-5,6-dimethyl-7- 0.50-1.08 (m, 6H + 6H′), 1.50 m, 3/1 oxo(4,7- 2H + 2H′), 2.07 (s, 3H + 3H′), dihydropyrazolo[1,5a]pyrimidin-2.23-2.65 (m, 5H + 5H′), 3.10 (br 2-yl))methyl]-N- s, 2H), 3.30 (br s,2H′), 4.83 (s, propyl(3- 2H), 4.50 (s, 2H′), 7.00-7.62 (m,fluorophenyl)carboxamide 4H + 4H′) 8 CH₃ CH₃ CH₃ Ethyl Propyl 3-FluoroN-[(3-ethyl-4,5,6- 0.68 (t, 3H), 0.90 (t, 3H′), 1.23 4/1trimethyl-7-oxo(4,7- (t, 3H), 1.05 (br s, 3H′), 1.60 (m,dihydropyrazolo[1,5a]pyrimidin- 2H + 2H′), 2.18 (s, 3H + 3H′), 2.402-yl))methyl]-N- (s, 3H + 3H′), 2.88 (q, 2H), 2.49 propyl(3- (q, 2H′),3.20 (t, 2H), 3.40 (br s, fluorophenyl)carboxamide 2H′), 3.83 (s, 2H0,3.77 (s, 2H′), 4.95 (s, 2H), 4.64 (s, 2H′), 7.05- 7.43 (m, 4H + 4H′) 9 HCH₃ CH3— Propyl secbutyl 3-Fluoro N-[(4,5-dimethyl-7-oxo-3- 0.76 (t,3H), 1.02 (t, 3H), 1.16 propyl(4,7- (d, 3H0, 1.40-1.89 (m, 4H), 2.35dihydropyrazolo[1,5a]pyrimidin- (s, 3H), 2.87 (t, 2H), 3.67-3.802-yl))methyl]-N- (m, 4H), 4.55 (d, 1H), 5.10 (d, (methylpropyl)(3- 1H),5.70 (s, 1H), 7.05-7.40 (m, fluorophenyl)carboxamide 4H) 10 H CH₃ CH₃Propyl (CH₃CH₂)₂ 3-Fluoro N-[(4,5-dimethyl-7-oxo-3- 0.75 (t, 6H), 0.87(t, 6H′), 1.02 5/1 CH— propyl(4,7- (t, 3H), 0.95 (t, 3H′), 1.40-1.60dihydropyrazolo[1,5a]pyrimidin- (m, 6H + 6H′), 2.35 (s, 3H + 3H′),2-yl))methyl]-N- 2.88 (t, 2H), 2.43 (t, 2H′), 3.48 (ethylpropyl)(3- (m,1H + 1H′), 3.77 (s, 3H), 3.70 fluorophenyl) carboxamide (s, 3H′), 4.80(s, 2H), 4.52 (s, 2H′), 5.69 (s, 1H + 1H′), 7.05-7.40 (m, 4H + 4H′) 11 HCH₃ CH₃ Propyl benzyl 3-Fluoro N-[(4,5-dimethyl-7-oxo-3- 1.00 (t, 3H),0.73 (br s, 3H′), 3/1 propyl(4,7- 1.58 (m, 2H), 1.23 (m, 2H′), 2.36dihydropyrazolo[1,5a]pyrimidin- (s, 3H + 3H′), 2.80 (t, 2H), 2.252-yl))methyl]-N- (br s, 2H′), 3.76 (s, 3H), 3.63 (s, benzyl(3- 3H′),4.68 (s, 2H), 4.53 (s, 2H′), fluorophenyl)carboxamide 4.84 (s, 2H +2H′), 5.73 (s, 1H + 1H′), 7.04-7.40 (m, 9H + 9H′) 12 CH₃ CH₃ H PropylPropyl 3-Fluoro N-[(5,6-dimethyl-7-oxo-3- 0.63-0.97 (m, 6H + 6H′),1.40-1.80 4/1 propyl(4,7- (m, 4H + 4H′), 2.05 (s, 3H + 3H′),dihydropyrazolo[1,5a]pyrimidin- 2.20-2.56 (m, 5H + 5H′), 3.24 (m,2-yl))methyl]-N- 2H + 2H′), 4.81 (s, 2H), 4.57 (s, propyl(3- 2H′),7.01-7.39 (m, 4H + 4H′) fluorophenyl)carboxamide 13 CH₃ CH₃ CH₃ PropylPropyl 3-Fluoro N-propyl-N-[(4,5,6- 0.67 (t, 3H), 0.83 (br s, 3H′), 4/1trimethyl-7-oxo-3- 1.03 (t, 3H), 0.88 (t, 3H′), 1.47- propyl(4,7- 1.67(m, 4H + 4H′), 2.20 (s, 3H + dihydropyrazolo[1,5a]pyrimidin- 3H′), 2.40(s, 3H + 3H′), 2.80 (t, 2-yl))methyl](3- 2H + 2H′), 3.20 (t, 2H), 3.42(br fluorophenyl)carboxamide s, 2H′), 3.81 (s, 3H), 3.72 (s, 3H′), 4.95(s, 2H), 4.65 (s, 2H′), 7.03-7.43 (m, 4H + 4H′) 14 H CH₃ H Ethylisobutyl 3-Chloro N-[(3-ethyl-5-methyl-7- 0.67 (d, 6H), 0.80-0.94 (m,6H′ + 3/1 oxo (4,7- 3H′), 1.05 (t, 3H), 2.00 (m 1H +dihydropyrazolo[1,5a]pyrimidin- 1H′), 2.25 (s, 3H + 3H′), 2.55 (q,2-yl))methyl]-N-(2- 2H), 2.33 (br s, 2H′), 3.09 (d, 2H),methylpropyl)(3- 3.20 (d, 2H′), 4.84 (s, 2H), 4.55chlorophenyl)carboxamide (s, 2H′), 5.59 (s, 1H), 5.62 (s, 1H′),7.20-7.40 (m, 4H + 4H′) 15 H CH₃ CH₃ Ethyl isobutyl 3-ChloroN-[(3-ethyl-4,5-dimethyl-7- 0.72 (d, 6H), 0.93 (d, 6H′), 3/1 oxo(4,7-1.25 (s, 3H), 1.05 (t, 3H′), 2.20 dihydropyrazolo[1,5a]pyrimidin- (m,1H + 1H′), 2.38 (s, 3H + 3H′), 2-yl))methyl]-N-(2- 2.87 (q, 2H), 2.49(q, 2H′), 3.10 methylpropyl)(3- (d, 2H), 3.25 (d, 2H′), 3.84 (s,chlorophenyl)carboxamide 3H), 3.72 (s, 3H′), 4.94 (s, 2H), 4.65 (s,2H′), 5.73 (s, 1H + 1H′), 7.23-7.50 (m, 4H + 4H′) 16 H CH₃ CH₃— Propylsecbutyl 3-Chloro N-[(4,5-dimethyl-7-oxo-3- 0.75 (t, 3H), 1.01 (t, 3H),1.15 propyl(4,7- (d, 3H), 1.40-1.85 (m, 4H), 2.34dihydropyrazolo[1,5a]pyrimidin- (s, 3H), 2.85 (t, 2H), 3.64-3.802-yl))methyl]-N- (m, 4H), 4.54 (d, 1H), 5.09 (d, (methylpropyl)(3- 1H),5.70 (s, 1H), 7.20-7.46 (m, chlorophenyl)carboxamide 4H) 17 H CH₃ CH₃Propyl (CH₃CH₂)₂ 3-Chloro N-[(4,5-dimethyl-7-oxo-3- 0.77 (t, 6H), 0.88(t, 6H′), 1.02 5/1 CH— propyl(4,7- (t, 3H + 3H′), 1.40-1.80 (m, 6H +dihydropyrazolo[1,5a]pyrimidin- 6H′), 2.35 (s, 3H + 3H′), 2.88 (t,2-yl))methyl]-N- 2H), 2.43 (t, 2H′), 3.47 (m, 1H + (ethylpropyl)(3-1H′), 3.78 (s, 3H), 3.68 (s, 3H′), chlorophenyl)carboxamide 4.80 (s,2H), 4.51 (s, 2H′), 5.69 (s, 1H + 1H′), 7.25-7.48 (m, 4H + 4H′) 18 H CH₃CH₃ Propyl benzyl 3-Chloro N-[(4,5-dimethyl-7-oxo-3- 1.00 (t, 3H), 0.73(br s, 3H′), 3/1 propyl(4,7- 1.58 (m, 2H), 1.23 (m, 2H′), 2.36dihydropyrazolo[1,5a]pyrimidin- (s, 3H + 3H′), 2.80 (t, 2H), 2.242-yl))methyl]-N- (br s, 2H′), 3.76 (s, 3H), 3.62 (s, benzyl(3- 3H′),4.67 (s, 2H), 4.49 (s, 2H′), chlorophenyl)carboxamide 4.84 (s, 2H +2H′), 5.72 (s, 1H + 1H′), 7.10-7.54 (m, 9H + 9H′) 19 CH₃ CH₃ H PropylPropyl 3-Chloro N-[(5,6-dimethyl-7-oxo-3- 0.63-0.92 (m, 6H + 6H′),1.40-1.60 3/1 propyl(4,7- (m, 4H + 4H′), 2.03 (s, 3H + 3H′),dihydropyrazolo[1,5a]pyrimidin- 2.23-2.55 (m, 5H + 5H′), 3.21 (m,2-yl))methyl]-N- 2H + 2H′), 4.76 (s, 2H), 4.52 (s, propyl(3- 2H′),7.20-7.40 (m, 4H + 4H′) chlorophenyl)carboxamide 20 CH₃ CH₃ CH₃ PropylPropyl 3-Chloro N-propyl-N-[(4,5,6- 0.68 (t, 3H), 0.83 (t, 3H′), 1.034/1 trimethyl-7-oxo-3- (t, 3H), 0.90 (t, 3H′), 1.40-1.63 propyl(4,7- (m,4H + 4H′), 2.20 (s, 3H + 3H′), dihydropyrazolo[1,5a]pyrimidin- 2.41 (s,3H + 3H′), 2.80 (t, 2H + 2-yl))methyl](3- 2H′), 3.20 (t, 2H + 2H′), 3.81(s, chlorophenyl)carboxamide 3H), 3.74 (s, 3H′), 4.96 (s, 2H), 4.61 (s,3H′), 7.20-7.40 (m, 4H + 4H′) 21 H CH₃ H Propyl isobutyl 2,5-N-[(5-methyl-7-oxo-3- 0.60-0.85 (m, 9H + 9H′), 1.49 (m, 2/1 Difluoropropyl(4,7- 2H + 2H′), 1.97 (m, 1H + 1H′),dihydropyrazolo[1,5a]pyrimidin- 2.04-2.60 (m, 5H + 5H′), 2.96 (d,2-yl))methyl]-N-(2- 2H + 2H′), 4.83 (s, 2H), 4.50 (s, methylpropyl)(2,5- 2H′), 5.60 (s, 1H + 1H′), 6.97-7.08 difluorophenyl)carboxamide (m,3H + 3H′) 22 H CH₃ CH₃ Propyl isobutyl 2,5- N-[(4,5-dimethyl-7-oxo-3-0.68 (d, 6H), 0.92 (d, 6H′), 1.02 3/1 Difluoro propyl(4,7- (t, 3H), 0.85(t, 3H′), 1.50 (m, 2H + dihydropyrazolo[1,5a]pyrimidin- 2H′), 2.21 (m,1H + 1H′), 2.40 2-yl))methyl]-N-(2- (s, 3H), 2.35 (s, 3H′), 2.76 (t,methylpropyl) (2,5- 2H), 2.43 (t, 2H′), 2.98 (d, 2H +difluorophenyl)carboxamide 2H′), 3.81 (s, 3H), 3.72 (s, 3H′), 4.97 (s,2H), 4.60 (s, 2H′), 5.73 (s, 1H + 1H′), 7.00-7.23 (m, 3H + 3H′) 23 H CH₃H Ethyl Ethyl 2,5- N-ethyl-N-[(3-ethyl-5- 0.83-1.13 (m, 6H + 6H′), 2.36(s, 3/1 Difluoro methyl-7-oxo(4,7- 3H), 2.32 (s, 3H′), 2.57 (q, 2H +dihydropyrazolo[1,5a]pyrimidin- 2H′), 3.20 (q, 2H + 2H′), 4.87 (s,2-yl))methyl](2,5- 2H), 4.52 (s, 2H′), 5.62 (s, 1H +difluorophenyl)carboxamide 1H′), 6.93-7.11 (m, 3H + 3H′) 24 H CH₃ CH₃Ethyl isobutyl 2,5- N-[(3-ethyl-4,5-dimethyl-7- 0.68 (d, 6H), 0.91 (d,6H′), 1.24 3/1 Difluoro oxo(4,7- (t, 3H), 1.05 (t, 3H′), 2.20 (m, 1H +dihydropyrazolo[1,5a]pyrimidin- 1H′), 2.37 (s, 3H), 2.34 (s,2-yl))methyl]-N-(2- 3H′), 2.83 (q, 2H), 2.50 (q, 2H′), methylpropyl)(2,5- 2.96 (d, 2H), 3.12 (m, 2H′), 3.80 difluorophenyl)carboxamide (s,3H), 3.74 (s, 3H′), 4.96 (s, 2H), 4.60 (s, 2H′), 5.71 (s, 1H), 5.69 (s,1H′), 6.75-7.00 (m, 2H + 2H′), 7.33-7.47 (m, 1H + 1H′) 25 H CH₃ CH₃Propyl secbutyl 2,5- N-[(4,5-dimethyl-7-oxo-3- 0.75 (t, 3H), 0.80 (t,3H′), 1.04 4/1 Difluoro propyl(4,7- (t, 3H), 0.91 (t, 3H′), 1.09 (d,dihydropyrazolo[1,5a]pyrimidin- 3H), 1.18 (d, 3H′), 1.40-1.69 (m,2-yl))methyl]-N- 4H + 4H′), 2.38 (s, 3H), 2.36 (s, (methylpropyl) (2,5-3H′), 2.85 (t, 2H), 2.45 (t, 2H′), difluorophenyl)carboxamide 3.60 (m,1H + 1H′), 3.80 (s, 3H), 3.70 (s, 3H′), 4.65 (d, 1H + 1H′), 5.20 (br s,1H + 1H′), 5.70 (s, 1H), 5.73 (s, 1H′), 7.01-7.25 (m, 3H + 3H′) 26 H CH₃CH₃ Propyl (CH₃CH₂)₂ 2,5- N-[(4,5-dimethyl-7-oxo-3- 0.72 (t, 6H), 0.88(br s, 6H′), 5/1 CH— Difluoro propyl(4,7- 1.03 (t, 3H + 3H′), 1.40-1.80(m, dihydropyrazolo[1,5a]pyrimidin- 6H + 6H′), 2.37 (s, 3H), 2.34 (s,2-yl))methyl]-N- 3H′), 2.83 (t, 2H), 2.45 (t, 2H′), (ethylpropyl) (2,5-3.28 (m, 1H + 1H′), 3.80 (s, 3H), difluorophenyl)carboxamide 3.68 (s,3H′), 4.9 (br d, 2H), 4.48 (s, 2H′), 5.71 (s, 1H + 1H′), 7.00- 7.33 (m,3H + 3H′) 27 H CH₃ CH₃ Propyl benzyl 2,5- N-[(4,5-dimethyl-7-oxo-3- 1.02(t, 3H), 0.71 (t, 3H′), 1.58 3/1 Difluoro propyl(4,7- (m, 2H), 1.25 (m,2H′), 2.38 (s, dihydropyrazolo[1,5a]pyrimidin- 3H), 2.35 (s, 3H′), 2.80(t, 2H), 2-yl))methyl]-N- 2.24 (t, 2H′), 3.78 (s, 3H), 3.60 benzyl(2,5-(s, 3H′), 4.55 (s, 2H), 4.49 (s, difluorophenyl)carboxamide 2H′), 4.89(s, 2H + 2H′), 5.74 (s, 1H + 1H′), 7.00-7.28 (m, 8H + 8H′) 28 CH₃ CH₃ HPropyl Propyl 2,5- N-[(5,6-dimethyl-7-oxo-3- 0.52-0.97 (m, 6H + 6H′),1.33-1.60 3/1 Difluoro propyl (4,7- (m, 4H + 4H′), 2.07 (s, 3H + 3H′),dihydropyrazolo[1,5a]pyrimidin- 2.20-2.60 (m, 5H + 5H′), 3.20 (m,2-yl))methyl]-N- 2H + 2H′), 4.84 (s, 2H), 4.46 (s, propyl(2,5- 2H′),6.87-7.10 (br s 3H + 3H′) difluorophenyl)carboxamide 29 CH₃ CH₃ CH₃—Propyl Propyl 2,5- N-propyl-N-[(4,5,6- 0.64 (t, 3H), 0.85 (t, 3H′), 1.053/1 Difluoro trimethyl-7-oxo-3- (t, 3H), 0.90 (t, 3H′), 1.30-1.68propyl(4,7- (m, 4H + 4H′), 2.20 (s, 3H), 2.16dihydropyrazolo[1,5a]pyrimidin- (s, 3H′), 2.40 (s, 3H), 2.36 (s,2-yl))methyl](2,5- 3H′), 2.76 (t, 2H), 2.44 (t, 2H′),difluorophenyl)carboxamide 3.10 (t, 2H + 2H′), 3.82 (s, 3H), 3.73 (t,3H′), 4.96 (s, 2H), 4.60 (s, 2H′), 7.00-7.24 (m, 3H + 3H′)

[0215] TABLE 2

No. R1 R2 R3 R4 R5 X Name ¹H NMR (CDCl3) δ 30 H CH₃ CH₃ Propyl isoButyl3-Fluoro N-[(7-methoxy-5-methyl-3- 0.75 (d, 6H), 1.00 (t, 3H), 1.70 (m,propyl(pyrazolo[1,5- 2H), 1.89 (m, 1H), 2.36 (s, 3H), 2.62a]pyrimidin-2-yl))methyl]- (t, 2H), 3.05 (d, 2H), 4.07 (s, 3H),N-(2-methylpropyl)(3- 4.93 (s, 2H), 5.98 (s, 1H), 7.07-7.45fluorophenyl)carboxamide (m, 4H) 31 H CH₃ CH₃ Propyl Propyl 3-FluoroN-[(7-methoxy-5-methyl-3- 0.73 (t, 3H), 1.00 (t, 3H), 1.49 (m,propyl(pyrazolo[1,5- 2H), 1.69 (m, 2H), 2.36 (s, 3H), 2.64a]pyrimidin-2-yl))methyl]- (t, 2H), 3.11 (t, 2H), 4.09 (s, 3H),N-propyl(3- 4.93 (s, 2H), 5.94 (s, 1H), 7.07-7.47fluorophenyl)carboxamide (m, 4H) 32 H CH₃ CH₃ Ethyl isoButyl 3-FluoroN-[(3-ethyl-7-methoxy-5- 0.74 (d, 6H), 1.27 (t, 3H), 1.89 (m,methyl(pyrazolo[1,5- 1H), 2.36 (s, 3H), 2.69 (q, 2H), 3.07a]pyrimidin-2-yl))methyl]- (d, 2H), 4.07 (s, 3H), 4.91 (s, 2H),N-(2-methylpropyl)(3- 5.98 (s, 1H0, 7.05-7.47 (m, 4H)fluorophenyl)carboxamide 33 H CH₃ CH₃ Ethyl isoButyl 3-ChloroN-[(3-ethyl-7-methoxy-5- 0.75 (d, 6H), 1.29 (t, 3H), 1.89 (m,methyl(pyrazolo[1,5- 1H), 2.36 (s, 3H), 2.69 (q, 2H), 3.05a]pyrimidin-2-yl))methyl]- (d, 2H), 4.08 (s, 3H), 4.92 (s, 2H),N-(2-methylpropyl)(3- 5.98 (s, 1H), 7.25-7.45 (m, 4H)chlorophenyl)carboxamide 34 H CH₃ CH₃ Propyl isoButyl 2,5-di-N-[(7-methoxy-5-methyl-3- 0.76 (d, 6H), 0.98 (t, 3H), 1.70 (m, fluoropropyl(pyrazolo[1,5- 2H), 1.85 (m, 1H), 2.36 (s, 3H), 2.62a]pyrimidin-2-yl))methyl]- (t, 2H), 2.95 (d, 2H), 4.09 (s, 3H),N-(2-methylpropyl)(2,5- 4.98 (br s, 2H), 5.96 (s, 1H), 7.04-difluorophenyl)carboxamide 7.20 (m, 3H) 35 H CH₃ CH₃ Ethyl isoButyl2,5-di- N-[(3-ethyl-7-methoxy-5- 0.73 (d, 6H), 1.27 (t, 3H), 1.87 (m,fluoro methyl(pyrazolo[1,5- 1H), 2.36 (s, 3H), 2.69 (q, 2H), 2.95a]pyrimidin-2-yl))methyl] (d, 2H), 4.09 (s, 3H), 4.96 (br s, 2H),N-(2-methylpropyl)(2,5- 5.96 (s, 1H), 6.84-7.02 (m, 2H), 7.40difluorophenyl) (m, 1H) carboxamide

[0216] TABLE III

No. R3 R4 R5 X Name ¹H NMR (CDCl3) δ H/H′ 36 H Propyl Propyl 3-FluoroN-[(8-oxo-3-propyl(4,5,6,7,8a- 0.64 (br s, 3H + 3H′), 0.98 (br s, 3H +3/1 pentahydrocyclopenta[2,1- 3H′), 1.40-1.60 (br s, 4H + 4H′), 2.09d]pyrazolo[1,5a]pyrimidin-2- (br s, 2H + 2H′), 2.50 (br s, 2H), 2.27yl))methyl]-N-propyl(3- (br s, 2H′), 2.69-2.95 (m, 4H + 4H′),fluorophenyl)carboxamide 3.14 (br s, 2H), 3.30 (br s, 2H′), 4.80 (s,2H), 4.54 (s, 2H′), 7.01-7.38 (m, 4H + 4H′) 37 CH₃ Propyl Propyl3-fluoro N-[(4-methyl-8-oxo-3- 0.69 (t, 3H), 0.84 (br s, 3H′), 1.02 3/1propyl(4,5,6,7,8a- (t, 3H), 0.90 (br s, 3H′), 1.47-1.67pentahydrocyclopenta[2,1- (m, 4H + 4H′), 2.16 (m, 2H + 2H′), 2.80d]pyrazolo[1,5a]pyrimidin-2- (t, 2H), 2.41 (br s, 2H′), 3.00 (t, 2H +yl))methyl]-N-propyl(3- 2H′), 2.93 (t, 2H + 2H′), 3.20 (t,fluorophenyl)carboxamide 2H), 3.42 (br s, 2H′), 3.80 (s, 3H), 3.73 (s,3H′), 4.95 (s, 2H), 4.64 (s, 2H′), 7.04-7.40 (m, 4H + 4H′) 38 H EthylPropyl 3-fluoro N-[(3-ethyl-8-oxo(4,5,6,7,8a- 0.63 (br s, 3H), 0.83 (brs, 3H′), 1.05 3/1 pentahydrocyclopenta[2,1- (br s, 3H), 0.90 (br s,3H′), 1.50 (br d]pyrazolo[1,5a]pyrimidin-2- s, 2H + 2H′), 2.11 (br s,2H + 2H′), yl))methyl]-N-propyl(3- 2.56 (br s, 2H), 2.31 (br s, 2H′),fluorophenyl)carboxamide 2.70-3.00 (m, 4H + 4H′), 3.20 (br s, 2H), 3.32(br s, 2H′), 4.83 (s, 2H), 4.55 (s, 2H′), 7.02-7.39 (m, 4H + 4H′) 39 CH₃Ethyl Propyl 3-fluoro N-[(3-ethyl-4-methyl-8- 0.67 (t, 3H), 0.89 (br s,3H′), 1.23 3/1 oxo(4,5,6,7,8a- (t, 3H), 1.05 (br s, 3H′), 1.60 (m, 2H +pentahydrocyclopenta[2,1- 2H′), 2.16 (m, 2H + 2H′), 2.85 (q,d]pyrazolo[1,5a]pyrimidin-2- 2H), 2.50 (br s, 2H′), 2.96 (t, 2H +yl))methyl]-N-propyl(3- 2H′), 3.02 (t, 2H + 2H′), 3.20 (t, 2H),fluorophenyl)carboxamide 3.40 (br s, 2H′), 3.82 (s, 3H), 3.72 (s, 3H′),4.96 (s, 2H), 4.65 (s, 2H′), 7.05-7.44 (m, 4H + 4H′) 40 H Ethyl Propyl3-Chloro N-[(3-ethyl-8-oxo(4,5,6,7,8a- 0.65 (br s, 3H), 0.84 (br s,3H′), 1.16 4/1 pentahydrocyclopenta[2,1- (br s, 3H), 0.91 (br s, 3H′),1.50 (br d]pyrazolo[1,5a]pyrimidin-2- s, 2H + 2H′), 2.11 (br s, 2H +2H′), yl))methyl]-N-propyl(3- 2.54 (br s, 2H), 2.30 (br s, 2H′),chlorophenyl)carboxamide 2.75-2.94 (m, 4H + 4H′), 3.20 (br s, 2H), 3.34(br s, 2H′), 4.84 (s, 2H), 4.56 (s, 2H′), 7.24-7.53 (m, 4H + 4H′) 41 CH₃Ethyl Propyl 3-Chloro N-[(3-ethyl-4-methyl-8- 0.69 (t, 3H), 0.90 (br s,3H′), 1.24 3/1 oxo(4,5,6,7,8a- (t, 3H), 1.04 (br s, 3H′), 1.60 (m, 2H +pentahydrocyclopenta[2,1- 2H′), 2.19 (m, 2H + 2H′), 2.85 (q,d]pyrazolo[1,5a]pyrimidin-2- 2H), 2.50 (br s, 2H′), 2.96 (t, 2H +yl))methyl]-N-propyl(3- 2H′), 3.01 (t, 2H + 2H′), 3.20 (t, 2H),chlorophenyl)carboxamide 3.40 (br s, 2H′), 3.83 (s, 3H), 3.77 (s, 3H′),4.95 (s, 2H), 4.63 (s, 2H′), 7.20-7.48 (m, 4H + 4H′) 42 H Ethyl Propyl2,5-difluoro N-[(3-ethyl-8-oxo(4,5,6,7,8a- 060-1.13 (m, 6H + 6H′), 1.50(m, 2H + 3/1 pentahydrocyclopenta[2,1- 2H′), 2.10 (br s, 2H + 2H′), 2.60(br d]pyrazolo[1,5a]pyrimidin-2- s, 2H + 2H′), 2.75-2.95 (m, 4H + 4H′),yl))methyl]-N-propyl(2,5- 3.08 (br s, 2H), 3.28 (q, 2H′), 4.87difluorophenyl)carboxamic (s, 2H), 4.52 (s, 2H′), 6.93-7.13 (br s, 3H +3H′) 43 CH₃ Ethyl Propyl 2,5-difluoro N-[(3-ethyl-4-methyl-8- 0.68 (t,3H), 0.88 (t, 3H′), 1.23 (t, 4/1 oxo(4,5,6,7,8a- 3H), 1.03 (t, 3H′),1.54 (m, 2H), 1.65 pentahydrocyclopenta[2,1- (m, 2H′), 2.18 (m, 2H +2H′), 2.85 (q, d]pyrazolo[1,5a]pyrimidin-2- 2H), 2.51 (q, 2H′), 2.95 (m,2H + 2H′), yl))methyl]-N-propyl(2,5- 3.00 (t, 2H + 2H′), 3.13 (t, 2H +2H′), difluorophenyl)carboxamide 3.83 (s, 3H), 3.75 (s, 3H′), 5.00 (s,2H), 4.60 (s, 2H′), 7.02-7.23 (m, 3H + 3H′)

Example 5 Ligand Binding Assay

[0217] The affinity of compounds of this invention for thebenzodiazepine site of the GABA_(A) receptor is demonstrated using abinding assay essentially described by Thomas and Tallman (J. Bio. Chem.1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).

[0218] Rat cortical tissue is dissected and homogenized in 25 volumes(w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissuehomogenate is centrifuged in the cold (4° C.) at 20,000×g for 20minutes. The supernatant is decanted, the pellet rehomogenized in thesame volume of buffer, and centrifuged again at 20,000×g. Thesupernatant of this centrifugation step is decanted and the pelletstored at −20° C. overnight. The pellet is then thawed and resuspendedin 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g andthe supernatant decanted. This wash step is repeated once. The pellet isfinally resuspended in 50 volumes of Buffer A.

[0219] Incubations contained 100 μl of tissue homogenate, 100 μl ofradioligand, (0.5 nM ³H-Ro15-1788 [³H-Flumazenil], specific activity 80Ci/mmol), and test compound or control (see below), and are brought to atotal volume of 500 μl with Buffer A. Incubations are maintained for 30min at 4° C. and then rapidly filtered through Whatman GFB filters toseparate free and bound ligand. Filters are washed twice with freshBuffer A and counted in a liquid scintillation counter. Nonspecificbinding (control) is determined by displacement of ³H Ro15-1788 with 10μM Diazepam (Research Biochemicals International, Natick, Mass.). Dataare collected in triplicate, averaged, and percent inhibition of totalspecific binding (Total Specific Binding=Total−Nonspecific) iscalculated for each compound.

[0220] A competition binding curve is generated with up to 11 pointsspanning the compound concentration range from 10⁻¹²M to 10⁻⁵M obtainedper curve by the method described above for determining percentinhibition. K_(i) values are calculated according the Cheng-Prussofequation. Each of the compounds of the above examples has a K_(i) of<1μM in this assay. Preferred compounds of the invention exhibit K_(i)values of less than 100 nM and more preferred compounds of the inventionexhibit K_(i) values of less than 10 nM.

Example 6 Electrophysiology

[0221] The following assay is used to determine if a compound of theinvention acts as an agonist, an antagonist, or an inverse agonist atthe benzodiazepine site of the GABA_(A) receptor.

[0222] Assays are carried out essentially as described in White andGurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett,Stirling, and Gregory (Receptors and Channels 3:1-5, 1995) withmodifications. Electrophysiological recordings are carried out using thetwo electrode voltage-clamp technique at a membrane holding potential of−70 mV. Xenopus Laevis oocytes are enzymatically isolated and injectedwith non-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γsubunits, respectively. Of the nine combinations of α, β and γ subunitsdescribed in the White et al. publications, preferred combinations areα₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂. Preferably all of the subunit cRNAsin each combination are human clones or all are rat clones. The sequenceof each of these cloned subunits is available from GENBANK, e.g., humanα₁, GENBANK accession no. X14766, human α₂, GENBANK accession no.A28100; human α₃, GENBANK accession no. A28102; human α₅, GENBANKaccession no. A28104; human β₂, GENBANK accession no. M82919; human β₃,GENBANK accession no. Z20136; human γ₂, GENBANK accession no. X15376;rat α₁, GENBANK accession no. L08490, rat α₂, GENBANK accession no.L08491; rat α₃, GENBANK accession no. L08492; rat α₅, GENBANK accessionno. L08494; rat β₂, GENBANK accession no. X15467; rat β₃, GENBANKaccession no. X15468; and rat γ₂, GENBANK accession no. L08497. For eachsubunit combination, sufficient message for each constituent subunit isinjected to provide current amplitudes of >10 nA when 1 μM GABA isapplied.

[0223] Compounds are evaluated against a GABA concentration that evokes<10% of the maximal evocable GABA current (e.g., 1 μM-9 μM). Each oocyteis exposed to increasing concentrations of a compound being evaluated(test compound) in order to evaluate a concentration/effectrelationship. Test compound efficacy is calculated as a percent-changein current amplitude: 100((Ic/I)−1), where Ic is the GABA evoked currentamplitude observed in the presence of test compound and I is the GABAevoked current amplitude observed in the absence of the test compound.

[0224] Specificity of a test compound for the benzodiazepine site isdetermined following completion of a concentration/effect curve. Afterwashing the oocyte sufficiently to remove previously applied testcompound, the oocyte is exposed to GABA+1 μM RO15-1788, followed byexposure to GABA+1 μM RO15-1788+test compound. Percent change due toaddition of compound is calculated as described above. Any percentchange observed in the presence of RO15-1788 is subtracted from thepercent changes in current amplitude observed in the absence of 1 μMRO15-1788. These net values are used for the calculation of averageefficacy and EC₅₀ values by standard methods. To evaluate averageefficacy and EC₅₀ values, the concentration/effect data are averagedacross cells and fit to the logistic equation.

Example 7 MDCK Cytotoxicity Assay

[0225] This Example illustrates the evaluation of compound toxicityusing a Madin Darby canine kidney (MDCK) cell cytoxicity assay.

[0226] 1 μL of test compound is added to each well of a clear bottom96-well plate (PACKARD, Meriden, Conn.) to give final concentration ofcompound in the assay of 10 micromolar, 100 micromolar or 200micromolar. Solvent without test compound is added to control wells.

[0227] MDCK cells, ATCC no. CCL-34 (American Type Culture Collection,Manassas, Va.), are maintained in sterile conditions following theinstructions in the ATCC production information sheet. Confluent MDCKcells are trypsinized, harvested, and diluted to a concentration of0.1×10⁶ cells/ml with warm (37° C.) medium (VITACELL Minimum EssentialMedium Eagle, ATCC catalog #30-2003). 100 μL of diluted cells is addedto each well, except for five standard curve control wells that contain100 μL of warm medium without cells. The plate is then incubated at 37°C. under 95% O₂, 5% CO₂ for 2 hours with constant shaking. Afterincubation, 50 μL of mammalian cell lysis solution is added per well,the wells are covered with PACKARD TOPSEAL stickers, and plates areshaken at approximately 700 rpm on a suitable shaker for 2 minutes.

[0228] Compounds causing toxicity will decrease ATP production, relativeto untreated cells. The PACKARD, (Meriden, Conn.) ATP-LITE-M LuminescentATP detection kit, product no. 6016941, is generally used according tothe manufacturer's instructions to measure ATP production in treated anduntreated MDCK cells. PACKARD ATP LITE-M reagents are allowed toequilibrate to room temperature. Once equilibrated, the lyophilizedsubstrate solution is reconstituted in 5.5 mL of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. For the five control wells, 10μL of serially diluted PACKARD standard is added to each of the standardcurve control wells to yield a final concentration in each subsequentwell of 200 nM, 100 nM, 50 nM, 25 nM and 12.5 nM. PACKARD substratesolution (50 μL) is added to all wells, which are then covered, and theplates are shaken at approximately 700 rpm on a suitable shaker for 2minutes. A white PACKARD sticker is attached to the bottom of each plateand samples are dark adapted by wrapping plates in foil and placing inthe dark for 10 minutes. Luminescence is then measured at 22° C. using aluminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillationand Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levelscalculated from the standard curve. ATP levels in cells treated withtest compound(s) are compared to the levels determined for untreatedcells. Cells treated with 10 μM of a preferred test compound exhibit ATPlevels that are at least 80%, preferably at least 90%, of the untreatedcells. When a 100 μM concentration of the test compound is used, cellstreated with preferred test compounds exhibit ATP levels that are atleast 50%, preferably at least 80%, of the ATP levels detected inuntreated cells.

[0229] It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3;

R₁ and R₂ are independently chosen from hydrogen, halogen, hydroxy,amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; or R₁ and R₂ togetherwith the atoms with which they are attached form a partially saturatedor unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein thering is optionally substituted by up to 5 substituents independentlychosen from halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; R₃,R₄ and R₅ are independently chosen from hydrogen; C₁-C₆ acyl; and C₁-C₆alkyl; wherein each C₁-C₆ acyl and C₁-C₆ alkyl is optionally substitutedwith up to three substituents independently chosen from halogen,hydroxy, halo(C₁-C₂)alkyl, halo (C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇cycloalkyl, phenyl, pyridyl, and pyrimidyl, wherein each of phenyl,pyridyl, and pyrimidyl is optionally substituted with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxyand amino; R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl; W is aryl or heteroaryl, each of which isoptionally substituted with up to 5 groups independently selected fromhydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo (C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.
 2. Acompound according to claim 1, wherein


3. A compound according to claim 2, wherein W is optionally substitutedheteroaryl.
 4. A compound according to claim 3, wherein W is pyridyl,pyrimidinyl, pyridizinyl, pyrrolyl, imidazolyl, pyrazolyl or thiophenyl,each of which is optionally substituted with up to 5 groupsindependently selected from hydrogen, halogen, hydroxy, amino, mono- ordi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl,and C₁-C₆ alkoxy.
 5. A compound according to claim 2, wherein W isoptionally substituted aryl.
 6. A compound according to claim 5, whereinW is phenyl optionally substituted with up to 5 groups independentlyselected from hydrogen, halogen, hydroxy, amino, mono- or di(C₁-C₆)alkylamino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆alkoxy.
 7. A compound according to claim 6, wherein R₄ and R₅ areindependently C₁-C₆ alkyl optionally substituted with 1 or 2substituents independently chosen from halogen, hydroxy,trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl,phenyl, pyridyl, and pyrimidyl, wherein each of phenyl, pyridyl, andpyrimidyl is optionally substituted with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxyand amino.
 8. A compound according to claim 6, wherein R₁ and R₂ areindependently chosen from hydrogen, halogen, hydroxy, amino, mono- anddi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyland C₁-C₆ alkoxy; and R₃, R₄ and R₅ are independently C₁-C₆ alkyl.
 9. Acompound according to claim 6, wherein R₁ and R₂ together with the atomswith which they are attached form a partially saturated or unsaturatedcarbocyclic ring of from 3 to 8 carbon atoms, wherein the ring isoptionally substituted by up to 5 substituents independently chosen fromhalogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; andR₃, R₄ and R₅ are independently H or C₁-C₆ alkyl.
 10. A compoundaccording to claim 9, wherein R₁ and R₂ together with the atoms withwhich they are attached form a cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cycloheptadienyl,phenyl, cyclooctadienyl, and cyclooctenyl, wherein each ring isoptionally substituted by up to 5 substituents independently chosen fromhalogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; andR₃, R₄ and R₅ are independently C₁-C₄ alkyl.
 11. A compound of theformula:

or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3;R₁ and R₂ are independently chosen from hydrogen, halogen, hydroxy,amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy; or R₁ and R₂ togetherwith the atoms with which they are attached form a partially saturatedor unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein thering is optionally substituted by up to 5 substituents independentlychosen from halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; R₃,R₄ and R₅ are independently chosen from (i) hydrogen; and (ii) C₁-C₆acyl and C₁-C₆ alkyl, optionally substituted with up to threesubstituents independently chosen from halogen, hydroxy,halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl,phenyl, pyridyl and pyrimidyl, wherein each of phenyl, pyridyl andpyrimidyl is optionally substituted with up to three groups selectedindependently from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy andamino; R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl; and R₁₀, R₁₁, X, Y and Z are independentlyselected from hydrogen, halogen, hydroxy, amino, mono- anddi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyland C₁-C₆ alkoxy.
 12. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3;R₁ and R₂ are independently chosen from hydrogen, halogen, hydroxy,amino, mono- and di(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy, or R₁ and R₂ togetherwith the atoms with which they are attached form a partially saturatedor unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein thering is optionally substituted by up to 5 substituents independentlychosen from halogen, hydroxy, amino, mono- and di(C₁-C₆)alkyl amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy; R₃,R₄ and R₅ are independently chosen from (i) hydrogen; and (ii) C₁-C₆acyl and C₁-C₆ alkyl, optionally substituted with up to threesubstituents independently chosen from halogen, hydroxy,halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl,phenyl, pyridyl and pyrimidyl, wherein each of phenyl, pyridyl andpyrimidyl is optionally substituted with up to three groups selectedindependently from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy andamino; R₆ and R₆′ are independently selected at each occurrence fromhydrogen and C₁-C₆ alkyl; and R₁₀, R₁₁, X, Y and Z are independentlyselected from hydrogen, halogen, hydroxy, amino, mono- anddi(C₁-C₆)alkyl amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyland C₁-C₆ alkoxy.
 13. A compound according to claim 8 of the formula:

or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3;R represents up to 5 groups independently chosen from hydrogen, halogen,hydroxy, amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl, andC₁-C₆ alkoxy; R₃, R₄ and R₅ are independently chosen from (i) hydrogen;and (ii) C₁-C₆ acyl and C₁-C₆ alkyl, optionally substituted with up tothree substituents independently chosen from halogen, hydroxy,halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl,phenyl, pyridyl and pyrimidyl, wherein each of phenyl, pyridyl andpyrimidyl is optionally substituted with up to three groups selectedindependently from halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy andamino; R₆ and R₆′ are independently chosen from hydrogen, methyl, andethyl; and R₁₀, R₁₁, X, Y and Z are independently selected fromhydrogen, halogen, hydroxy, amino, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,C₁-C₆ alkyl and C₁-C₆ alkoxy.
 14. A compound according to claim 13 ofthe formula:

or a pharmaceutically acceptable salt thereof, wherein: R₃, R₄ and R₅are independently chosen from (i) hydrogen; and (ii) C₁-C₆ acyl andC₁-C₆ alkyl, optionally substituted with up to three substituentsindependently chosen from halogen, hydroxy, halo(C₁-C₂)alkyl,halo(C₁-C₂)alkoxy, methoxy, ethoxy, C₃-C₇ cycloalkyl, phenyl, pyridyland pyrimidyl, wherein each of phenyl, pyridyl and pyrimidyl isoptionally substituted with up to three groups selected independentlyfrom halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxy and amino; R₁₀, R₁₁, X,Y and Z are selected from hydrogen, halogen, hydroxy, amino,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy.
 15. Acompound according to claim 14, wherein: R₃ is hydrogen, methyl orethyl; R₄ and R₅ are independently C₂-C₆ alkyl; and R₁₀, R₁₁, X, W, Yand Z are independently hydrogen, halogen or methyl.
 16. A compoundaccording to claim 11, wherein: n is 1; and R₁ and R₂ are independentlychosen from hydrogen, halogen, hydroxy, amino, halo(C₁-C₆) alkyl,halo(C₁-C₆) alkoxy, C₁-C₆ alkyl and C₁-C₆ alkoxy.
 17. A compoundaccording to claim 16, wherein: R₁, R₂, and R₃ are independently chosenfrom hydrogen, methyl, and ethyl; R₄ and R₅ are independently chosenfrom C₂-C₆ alkyl and benzyl; R₁₀, R₁₁, X, Y and Z are independentlyselected from hydrogen, halogen and methyl; and R₆ and R₆′ are bothhydrogen.
 18. A compound according to claim 11, wherein n is
 1. 19. Acompound according to claim 18, wherein: R₁ and R₂ are independentlychosen from hydrogen, methyl and ethyl; R₃ is methyl or ethyl; R₆ andR₆′ are both hydrogen; and R₁₀, R₁₁, X, W, Y and Z are independentlychosen from hydrogen, halogen, methyl, and methoxy.
 20. A compoundaccording to claim 1, which isN-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[l,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.21. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.
 22. Acompound according to claim 1, which isN-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide.23. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide.24. A compound according to claim 1, which isN-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide.25. A compound according to claim 1, which isN-[(4-ethyl-5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.26. A compound according to claim 1, which isN-[(3-ethyl-5,6-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.27. A compound according to claim 1, which isN-[(3-ethyl-4,5,6-trimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.28. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(3-fluorophenyl)carboxamide.29. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(3-fluorophenyl)carboxamide.30. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(3-fluorophenyl)carboxamide.31. A compound according to claim 1, which isN-[(5,6-dimethyl-7-oxo-3-propyl(4,7a-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.32. A compound according to claim 1, which isN-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](3-fluorophenyl)carboxamide.
 33. A compoundaccording to claim 1, which isN-[(3-ethyl-5-methyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3chlorophenyl)carboxamide.34. A compound according to claim 1, which isN-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-chlorophenyl)carboxamide.35. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(3-chlorophenyl)carboxamide.36. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(3-chlorophenyl)carboxamide.37. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(3-chlorophenyl)carboxamide.38. A compound according to claim 1, which isN-[(5,6-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide.39. A compound according to claim 1, which isN-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](3-chlorophenyl)carboxamide.
 40. A compoundaccording to claim 1, which isN-[(5-methyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide.
 41. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide.
 42. A compound according to claim 1, which isN-ethyl-N-[(3-ethyl-5-methyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](2,5-difluorophenyl)carboxamide.43. A compound according to claim 1, which isN-[(3-ethyl-4,5-dimethyl-7-oxo(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide.44. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(methylpropyl)(2,5-difluorophenyl)carboxamide.
 45. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-(ethylpropyl)(2,5-difluorophenyl)carboxamide.46. A compound according to claim 1, which isN-[(4,5-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-benzyl(2,5-difluorophenyl)carboxamide.47. A compound according to claim 1, which isN-[(5,6-dimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyll-N-propyl(2,5-difluorophenyl)carboxamide.48. A compound according to claim 1, which isN-propyl-N-[(4,5,6-trimethyl-7-oxo-3-propyl(4,7-dihydropyrazolo[1,5a]pyrimidin-2-yl))methyl](2,5-difluorophenyl)carboxamide.
 49. Acompound according to claim 1, which isN-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyi)(3-fluorophenyl)carboxamide.
 50. A compound according to claim 1, which isN-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.51. A compound according to claim 1, which isN-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-fluorophenyl)carboxamide.
 52. A compound according to claim 1, which isN-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(3-chlorophenyl)carboxamide.
 53. A compound according to claim 1, which isN-[(7-methoxy-5-methyl-3-propyl(pyrazolo[1,5-a]pyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide.
 54. A compound according to claim 1, which isN-[(3-ethyl-7-methoxy-5-methyl(pyrazolo[1,5-alpyrimidin-2-yl))methyl]-N-(2-methylpropyl)(2,5-difluorophenyl)carboxamide.
 55. A compound according to claim 1, which isN-[(8-oxo-3-propyl(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.
 56. A compound according to claim 1, which isN-[(4-methyl-8-oxo-3-propyl(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yi))methyl]-N-propyl(3-fluorophenyl)carboxamide.
 57. A compound according to claim 1, which isN-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.
 58. A compound according to claim 1, which isN-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-fluorophenyl)carboxamide.
 59. A compound according to claim 1, which isN-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide.
 60. A compound according to claim 1, which isN-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(3-chlorophenyl)carboxamide.
 61. A compound according to claim 1, which isN-[(3-ethyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[1,5a]pyrimidin-2-yl))methyl]-N-propyl(2,5-difluorophenyl)carboxamide.62. A compound according to claim 1, which isN-[(3-ethyl-4-methyl-8-oxo(4,5,6,7,8a-pentahydrocyclopenta[2,1-d]pyrazolo[l,5a]pyrimidin-2-yl))methyl]-N-propyl(2,5-difluorophenyl)carboxamide.63. A pharmaceutical composition comprising a compound of claim 1 incombination with a physiologically acceptable carrier or excipient. 64.The pharmaceutical composition of claim 63 wherein the pharmaceuticalcomposition is formulated as an injectable fluid, an aerosol, a cream, agel, a pill, a capsule, a syrup, or a transdermal patch.
 65. A methodfor the treatment of anxiety, depression, a sleep disorder, attentiondeficit disorder, or Alzheimer's dementia, comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim
 1. 66. A method for potentiating a therapeuticeffect of a CNS agent, comprising administering to a patient a CNS agentand a compound of claim
 1. 67. A method for determining the presence orabsence of GABA_(A) receptor in a sample, comprising: (a) contacting asample with a compound of claim 1 under conditions that permit bindingof the compound to GABA_(A) receptor; and (b) detecting a level ofcompound bound to GABA_(A) receptor, and therefrom determining thepresence or absence of GABA_(A) receptor in the sample.
 68. A methodaccording to claim 67, wherein the compound is radiolabeled, and whereinthe step of detection comprises: (i) separating unbound compound frombound compound; and (ii) detecting the presence or absence of boundcompound in the sample.
 69. The method of claim 68 wherein the presenceor absence of bound compound is detected using autoradiography.
 70. Amethod for altering the signal-transducing activity of GABA_(A)receptor, comprising contacting a cell expressing GABA_(A) receptor witha compound of claim 1 in an amount sufficient to detectably alter theelectrophysiology of the cell, and thereby altering GABA_(A) receptorsignal-transducing activity.
 71. The method of claim 70 wherein the cellrecombinantly expresses a heterologous GABA_(A) receptor, and whereinthe alteration of the electrophysiology of the cell is detected byintracellular recording or patch clamp recording.
 72. The method ofclaim 70 wherein the cell is a neuronal cell that is contacted in vivoin an animal, the solution is a body fluid, and the alteration in theelectrophysiology of the cell is detected as a change in the animal'sbehavior.
 73. The method of claim 72 wherein the animal is a human, thecell is a brain cell, and the fluid is cerebrospinal fluid.
 74. Apackaged pharmaceutical composition comprising the pharmaceuticalcomposition of claim 63 in a container and instructions for using thecomposition to treat a patient suffering from anxiety, depression, asleep disorder, attention deficit disorder, or Alzheimer's dementia. 75.A compound according to claim 1 wherein in an assay of GABA_(A) receptorbinding the compound exhibits an K_(l) of 1 micromolar or less.
 76. Acompound according to claim 1 wherein in an assay of GABA_(A) receptorbinding the compound exhibits an Kl of 100 nanomolar or less.
 77. Acompound according to claim 1 wherein in an assay of GABA_(A) receptorbinding the compound exhibits an K_(l) of 10 nanomolar or less.
 78. Theuse of a compound according to claim 1 for the manufacture of amedicament for the treatment of anxiety, depression, a sleep disorder,an attention deficit disorder, or Alzheimer's dementia.